Clinical effectiveness and safety of amlodipine/losartan‐based single‐pill combination therapy in patients with hypertension: Findings from real‐world, multicenter observational databases

Abstract Various single‐pill combinations (SPCs) have been introduced to improve drug compliance and clinical efficacy. However, there is a lack of real‐world evidence regarding the effectiveness of these SPCs for hypertension. This study evaluated the real‐world clinical efficacy and safety of amlodipine/losartan‐based SPC therapies in patients with hypertension in a real‐world setting. A total of 15 538 patients treated with amlodipine/losartan‐based SPCs [amlodipine + losartan (AL), amlodipine + losartan + rosuvastatin (ALR), and amlodipine + losartan + chlorthalidone (ALC)] were selected from the database of three tertiary hospitals in Korea. The efficacy endpoints were target blood pressure (BP) and low‐density lipoprotein cholesterol (LDL‐C) achievement rates. Safety was evaluated based on laboratory parameters. Drug adherence was defined as the proportion of medication days covered (PDC). The target BP attainment rate was above 90% and was similar among the three groups. Although many patients in the AL and ALC groups took statins, the target LDL‐C attainment rate was significantly higher in the ALR group than in the AL and ALC groups. Safety endpoints were not significantly different among the groups, except serum uric acid level and incidence rate of new‐onset hyperuricemia, which were significantly lower in the AL and ALR groups than in the ALC group. The PDC was > 90% in all groups. In the real‐world hypertensive patients, amlodipine/losartan‐based SPC therapy demonstrated good target BP achievement rates. Especially, rosuvastatin‐combination SPC showed better target LDL‐C goal achievement rate compared to the other SPCs. All three amlodipine/losartan‐based SPC had excellent drug adherence.


INTRODUCTION
The prevalence of hypertension is continuously increasing and is expected to reach approximately 1.56 billion worldwide by 2025. 1 In Korea, the number of patients with hypertension is continuously increasing and has exceeded 12 million; however, only 9 million take antihypertensive agents and only 6.5 million of them regularly visit a physician for treatment. 2 The maintenance of appropriate blood pressure (BP) [systolic BP (SBP) < 140 mmHg or diastolic BP (DBP) < 90 mmHg] in patients with hypertension undergoing treatment is a challenging issue to date. Many patients with hypertension require at least two antihypertensive drugs to achieve their target BP. 3 In Korea, 43.2% of the patients undergoing treatment for hypertension take two antihypertensive drugs, and 16.1% are on three or more antihypertensive medications. 2 Moreover, most patients with hypertension take additional medications for the comorbidities, among which, dyslipidemia is one of the most common. Thus, 53.8% of the patients undergoing treatment for hypertension also take antilipidemic medication.
Pill burden in these patients may lead to non-adherence to drug intake, which makes it difficult to control BP as well as overall cardiovascular risk factors. A meta-analysis revealed that poor drug adherence was associated with an increased risk of stroke in patients with hypertension. 4 Thus, the 2018 European guidelines for hypertension emphasized that drug adherence is an important factor in BP management and recommended the preemptive use of single-pill combinations (SPCs) to simplify drug regimens. 5 Among drug combination regimens, the combination of reninangiotensin system inhibitors and calcium channel blockers (CCBs) has been studied for their cardiovascular protection. 6 In addition to cardiovascular protection, angiotensin II receptor blockers (ARBs) have comparable BP-lowering effects and improve peripheral edema caused by CCBs. 7 In Korea, 61.1% of the patients with hypertension and taking two antihypertensive medications are treated with a combination of renin-angiotensin system inhibitors (in particular, ARBs) and CCBs. 2 Amlodipine (68%), among CCBs, and losartan (27%), among ARBs, are the most commonly prescribed antihypertensive agents in each class, according to the Korean healthcare data system. The combination of these two drugs have has been shown to be effective and safe for hypertension management. 8,9 In addi-

Study design
This was a multicenter, retrospective, observational, and cohort study. For safety analysis, we included all patients who had been prescribed amlodipine/losartan-based SPCs at least once (n = 15 538).
A total of 13 239 patients were included in the efficacy analysis after excluding patients who had been prescribed amlodipine/losartanbased combination pills for less than 4 weeks (n = 2245). If a patient was re-prescribed amlodipine/losartan-based SPCs after more than one year of "pill-vacation," only the re-prescription data were included.

Efficacy assessment
BP and lipid profiles [total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides] were used to assess the efficacy of amlodipine/

F I G U R E 1 Study schema
The safety endpoints were defined as new-onset hypotension, hypokalemia, hyperuricemia, and impaired renal function based on serum creatinine levels, proteinuria grade, and impaired fasting glucose level. The efficacy endpoints were defined by the target blood pressure and LDL-C attainment rates. Abbreviations: AL, amlodipine/losartan single-pill combination group; ALC, amlodipine/losartan/chlorthalidone single-pill combination group; ALR, amlodipine/losartan/rosuvastatin single-pill combination group; BP, blood pressure; HDL, high-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; SPC, single-pill combination

Safety assessment
BP and laboratory findings were used to assess the safety of the amlodipine/losartan-based SPCs. Hypotension was defined as SBP < 90 mmHg. Hypokalemia was defined as serum potassium level ≤ 3.0 mmol/L. Serum uric acid level > 6.5 mg/dL was defined as hyperuricemia. Fasting plasma glucose level > 100 mg/dL was defined as impaired fasting glucose level. Renal adverse event was defined as an increase in serum creatinine level (> 0.4 mg/dL) from baseline. The urine protein dipstick test was used to assess proteinuria, and an individual's urine protein level was defined as "worsening" if the result of urine dipstick test increased by more than one.

Assessment of drug adherence
Adherence to amlodipine/losartan-based SPCs was assessed using the proportion of days covered (PDC). 13 PDC was calculated as the total number of medication-covered days, the sum of the total number of prescription days for drugs during the follow-up period, divided by the number of days of drug enrollment, which was defined as the period between the first prescription day and the last day of administration of amlodipine/losartan-based SPCs. Because of the difficulty of tracking the days patients took the prescribed drugs precisely, if the patients revisited to refill their drugs, it was considered that the patients have had taken all of the previously prescribed medications. Pill splitting or doubling of pills from previous prescriptions was not considered. In the case of an early refill, the covered days were calculated by adjusting the number of overlapping days.

Other definitions
Diabetes mellitus was defined when patients had been diagnosed with

RESULTS
The baseline characteristics of the study participants are presented in Age ( or TIA) were more prevalent, in addition to higher body mass index, in the 3-drug combination pill groups (ALC and ALR groups) than in the AL group. In addition, chronic kidney disease was less frequently observed in the ALR group than in the other two groups. More than 50% of the patients in all groups were taking antihypertensive medications before the start of amlodipine/losartan-based SPCs; in particular, the proportion of such patients was the highest in the ALC group. In contrast, the proportion of patients who were previously taking antilipidemic medications before starting amlodipine/losartan-based SPCs was the lowest in the ALR group (rosuvastatin combination group). The total number of pills consumed by patients was significantly lower in the three-drug combination pill groups (ALC and ALR groups) than in the two-drug combination pill group (AL group) (p < .01).
The mean follow-up duration was 49.2 days for the short-term efficacy analysis and 330.0 days for the long-term analysis. Both SBP and DBP were significantly reduced during the short-term efficacy analysis (−9.7 mmHg for SBP and −5.9 mm g for DBP, p < .05) (Figure 2). Reduction in BP during short-term analysis was maintained in the long-term analysis (−8.5 mm Hg for SBP and −5.9 mm Hg for DBP, p < .05). Among all groups, the ALC group had the highest baseline SBP and DBP; therefore, despite the greatest decrease in BP in the ALC group, SBP was still higher in the ALC group than in the other two groups during the shortterm efficacy analysis. Notably, during the long-term efficacy analysis, these differences were reduced and target BP attainment rates were similar among the three groups; this may be due to the remarkable BPlowering effect observed in the ALC group. In Conclusion, the target BP attainment rate of amlodipine/losartan-based SPCs was 93.4% in the long-term efficacy analysis.
Baseline blood lipid profiles were found to differ among the groups.
Total cholesterol, LDL-C, and triglyceride levels were significantly improved in all groups (p < .05). In the long-term efficacy analysis, total cholesterol level was 23.7 mg/dL lower than the baseline in the ALR; however, in the AL group and ALC group, total cholesterol levels were 16.2 and 17.6 mg/dL, respectively. Similarly, LDL-C level was 22.5 mg/dL lower than the baseline in the ALR group in the long-term efficacy analysis, whereas the differences in the AL and ALC groups were 15.0 and 14.3 mg/dL, respectively. The ALR group had the lowest total cholesterol and LDL-C levels among the three groups during both the short-and long-term follow-up periods. Moreover, the target LDL-C attainment rate was the highest in the ALR group during both the short-term and long-term analyses. Notably, a significant proportion of patients in the AL and ALC groups were also taking statins (38.9% and 61.2%, respectively). We performed a separate analysis for patients taking statins in the AL and ALC groups and patients in the ALR group. The target LDL-C attainment rate of the ALR group was the highest (89.1%) during the long-term efficacy analysis. The AL and ALC groups had rates of 74.8% and 83.6%, respectively (p < .01). Table 2 presents the safety profiles of the three groups. The incidence rate of new-onset hypotension did not significantly differ among the groups. The baseline serum potassium level was slightly lower during follow-up in the ALC group than in the other groups. The incidence rate of new-onset, severe hypokalemia (< 3.0 mmol/L) was statistically insignificant. The follow-up serum uric acid level and the inci-dence rate of new-onset hyperuricemia were significantly lower in the AL and ALR groups than in the ALC group. Although follow-up plasma glucose levels were higher in the ALC group than in the other groups, the incidence rates of new-onset impaired fasting glucose were not significantly different among the groups. Baseline and follow-up serum creatinine levels were higher in the AL group than in the other groups.
The incidence rate of a clinically significant increase in serum creatinine level and worsening of proteinuria grade were statistically insignificant among the groups.
The PDC for the amlodipine/losartan-based SPCs is shown in Figure

DISCUSSION
This study was carried out to determine the efficacy and safety profiles of amlodipine/losartan-based SPCs in patients with hypertension in a real-world clinical setting. This study is the first and the largest realworld long-term observational study of the three amlodipine/losartan based SPCs using electronic health record data. From this study, we found several clinical perspectives for hypertensive patients. First, the three-drug combination pill groups (ALC and ALR groups) had a lower total pill burden and higher drug adherence than the two-drug combination pill group (AL group). Total pill number was lowered more than 1 in the three-drug combination pill groups compared to the two-drug combination pill group. The PDC in the three-drug combination groups was higher compared to the two-drug combination group (95.0% vs 90.7%). Second, all three groups treated with amlodipine/losartanbased SPCs had similar excellent BP control despite different baseline characteristics. Target BP achievement rates were more than 90% in all three groups. Third, ALR group of statin-containing SPC displayed the greatest benefits for dyslipidemia control. Target LDL-C achievement rate was the highest as 89.1% in the ALR group. Forth, all three groups showed good safety profiles.

F I G U R E 3 Proportion of days covered for amlodipine/losartan-based SPCs
Abbreviations: AL, amlodipine + losartan; ALC, amlodipine + losartan + chlorthalidone; ALR, amlodipine + losartan + rosuvastatin; PDC, proportion of days covered; SPC, single-pill combination contributes to superior BP control in patients with hypertension. 18 The PDC for amlodipine/losartan-based SPCs in this study was 91.5%, which was either comparable to or higher than that reported in previous studies on SPCs. [19][20][21] Because dyslipidemia is a chronic disease associated with no symptoms and has a slow progression, many patients with dyslipidemia do not fully understand the need for treatment. Therefore, a selection bias may have been present. Multivariate logistic regression analysis showed that ALR would be an independent predictor for the target LDL-C achievement after adjusting the baseline characteristics (odd ratio 2.32, 95% confidence interval 1.09-4.93, p = .03).
However, it is more worthwhile to elaborate the clinical efficacy, safety, and drug adherence of the three amlodipine/losartan-based SPCs than to compare among these three agents. As there are various clinical spectrums of hypertensive patients, the real-world clinical data of the three different SPCs of the present study will be able to precisely identify the strengths and weaknesses of each SPC and further improve the quality of clinical treatment for the patients with hypertension.

CONCLUSIONS
To the best of our knowledge, this is the first real-world longterm observational study of three amlodipine/losartan-based SPCs.
Amlodipine/losartan-based SPC therapy demonstrated good target BP achievement rates. Rosuvastatin-combination SPC showed better target LDL-C goal achievement rate compared to the other SPCs. All three amlodipine/losartan-based SPCs showed good efficacy, safety, and excellent drug adherence. Altogether, the findings of the present study will provide guidance for reframing the detailed clinical applications of SPC in patients with hypertension taking multiple pills.