https://orcid.org/0000-0002-8251-4480
ABSTRACT
Methods
: The home blood pressure control by a single-pill combination of cilnidipine and valsartan (HOPE-Combi) survey sought to evaluate the safety and efficacy of cilnidipine 10 mg/valsartan 80 mg single-pill combination (SPC of Cil/Val) treatment in patients with hypertension for over 12 months. Of 2622 subjects’ data; we analyzed 2572 cases for safety and 2372 cases for efficacy.
Results
Adverse drug reaction (ADR) incidence rate was 3.77% (97 of 2572 patients). The frequency of ADRs did not differ between patients aged <75 years and those aged ≥75 years (3.70% vs. 3.93%, respectively); between patients with and without chronic liver disease (CLD; 6.44% vs. 3.54%, respectively); and between patients with and without chronic kidney disease (CKD; 5.26% vs. 3.59%, respectively). Office systolic blood pressure (BP) was reduced from 149.5 ± 19.6 mmHg to 133.5 ± 14.8 mmHg (−15.8 mmHg, P < .01); pulse rate was also reduced 75.5 ± 12.2 bpm to 73.5 ± 11.3 bpm (−1.8 bpm, P < .01) after 12 months.
Conclusions
: The SPC of Cil/Val was safe and effective in treating BP of hypertensive patients in real-world settings.
Introduction
The treatment regimen for any chronic disease should be simple to improve the likelihood of adherence to the prescribed medication. For the management of hypertension, the most common therapeutic strategy is the initiation of antihypertensive drug monotherapy to achieve optimal blood pressure (BP). However, to achieve a more potent BP lowering effect, a combination of antihypertensive drugs from different classes should be considered (Citation1,Citation2). Combining two or three antihypertensive drugs at a fixed dose in a single tablet helps to reduce the number of pills that needs to be taken daily, resulting in improved adherence, which is notably low in patients with hypertension (Citation3,Citation4). In addition, fixed-dose combination drugs also improve the rate of BP control (Citation5,Citation6). All recent European, American, and Asian hypertension guidelines recommend the use of an antihypertensive in the form of a fixed-dose, single-pill combination (SPC) when multidrug therapy is indicated (Citation7–Citation9). Cilnidipine, a calcium channel blocker, inhibits L-type and N-type calcium channels (Citation10,Citation11). Valsartan is an angiotensin II receptor blocker (Citation12). ATEDIO® Combination Tablet, an SPC of cilnidipine 10 mg and valsartan 80 mg (SPC of Cil/Val), was approved by the Ministry of Health, Labor and Welfare of Japan in March 2014. However, the safety and efficacy of SPC of Cil/Val has not been evaluated in real-world settings. The home blood pressure (HBP) control by a single-pill combination of cilnidipine and valsartan (HOPE-Combi) survey aimed to assess the real-world safety and efficacy of the SPC of Cil/Val in patients with hypertension. Moreover, BP control was investigated according to the target BP level recommended in The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH) 2014 (Citation1) or JSH 2019 (Citation2).
Methods
Study design and patients
The Ministry of Health, Labor and Welfare of Japan Government required particular emphasis on the safety and efficacy of the SPC of Cil/Val in the patients ≥75 years of age, those with chronic liver disease (CLD), and those with chronic kidney disease (CKD) in post-marketing survey, because the safety and efficacy of the SPC of Cil/Val have not been investigated enough in clinical trials as required for new drug approval. The protocol for the HOPE-Combi survey was approved by the Ministry of Health, Labor and Welfare of the Japan Government. This survey was conducted in conformity with the Japanese Ministry directive on Good Post-marketing Study Practice guidelines, which regulates post-marketing surveillance activities. In compliance with these regulations, the need for informed consent from patients was waived. In addition, this survey was conducted with the approval of the institutional review board and ethics committee of each participating medical institution, if needed. It was registered as a post-marketing survey in the University Hospital Medical Information Network (UMIN000037536). This study was a single-arm, multi-center, post-marketing, prospective observational survey, conducted from October 2014 to July 2017. In HOPE-Combi, a contract for a post-marketing survey between the medical institution and MOCHIDA PHARMACEUTICAL CO., LTD was needed. The inclusion criteria were hypertensive patients who were administered the SPC of Cil/Val for the first time, and there were no exclusion criteria (BP level, age, comorbidities, medical history, etc.). The physician had to register the survey data within 15 days of initiation of the SPC of Cil/Val treatment in each patient after the conclusion of the HOPE-Combi contract. According to the label, the SPC of Cil/Val should be taken orally once daily after breakfast by adult patients, and is not typically used as a first-line drug for treating hypertension. Subjects were enrolled from 389 regional centers across 47 prefectures of Japan from October 2014 to February 2016. The observational period was 12 months, and there were five observation time points: baseline, 3, 6, 9, and 12 months; BP was measured at each visit to the clinic and at home. Office BP (OBP) was measured according to the JSH 2014 (Citation1). OBP was measured by maintaining the arm-cuff position at the heart level while resting in a seated position, by the auscultatory method using a sphygmomanometer, but the use of an automatic sphygmomanometer was also permitted. All patients received instructions from the physicians regarding measurement of HBP as per the guidelines recommended by the Japanese Society of Hypertension for self-monitoring of BP at home (Citation13). Each patient used an electronic cuff oscillometric device approved by the Ministry of Health, Labor and Welfare, Japan, and recorded HBP in a notebook specialized for BP measurements. Individual data of HBP were determined as a 3-day average of BP measured once early in the morning and once just before going to bed. After the observation period was complete, all data (patient demographics, adverse events, baseline and follow-up data, including OBP and HBP, etc.) that was entered by the doctor via the Electronic Data Capture system (ADDIN, INTAGE Healthcare Inc., Tokyo, Japan) was collated. The frequency and severity of adverse drug reactions (ADRs) was evaluated. ADRs were defined as an adverse event with a possible causal relationship with the SPC of Cil/Val. The Medical Dictionary for Regulatory Activities/J version 20.1 was used to code the ADRs. Serious ADR was defined as: (1) death, (2) disability, (3) may lead to disability, (4) may lead to death, (5) hospitalization for treatment or extension of hospital stay, (6) serious according to (1) to (5) as mentioned above, (7) congenital diseases or abnormalities in later generations. A target level for BP control was not stipulated, and there were no limitations on the class or dose of pre-treatment or concomitant antihypertensive medications. Morning home systolic blood pressure (MHSBP) values of <135 mmHg with office systolic blood pressure (OSBP) of <140 mmHg was classified as “normotension,” whereas MSHBP values of ≥135 mmHg with OSBP of ≥140 mmHg was classified as “sustained hypertension,” according to the JSH 2014 (Citation1). The proportions of patients that achieved the OBP and HBP (used morning HBP) target levels were calculated according to the target BP levels recommended in JSH 2014 (Citation1) or JSH 2019 (Citation2). As clinical characteristics of the patients were complex, the suitable target BP level for individual patients was based on their age and/or comorbidities, as described in Supplementary Table 1A and 1B (A: a precise target BP, B: not essential in judgment for achieving their target BP level, C; excluded in judgment for achieving their target BP level). The precise results of the effects of the SPC of Cil/Val in controlling morning HBP are being submitted to another journal (Citation14).
Endpoints
The primary endpoint of this survey was the safety of the SPC of Cil/Val in hypertensive patients. Safety, according to the reported ADRs and serious ADRs, was evaluated for the overall survey. The frequency of ADRs was compared between patients ≥75 years of age and <75 years of age, those with/without CLD, and those with/without CKD. Patients whose survey sheets were not collected were excluded from the safety analysis. Patients who did not visit the medical institute after the initial visit, and who were not registered within 15 days of the first prescription date were also excluded. The effectiveness of the SPC of Cil/Val was also investigated. The primary efficacy variable in this survey was a change in OBP from baseline at 3, 6, 9, and 12 months. The secondary efficacy variable was a change in office pulse rate (OPR) from baseline to 12 months in all patients, those with a baseline OPR ≥75 bpm and <85 bpm, and those with a baseline OPR ≥85 bpm, based on our previous report (Citation15), which divided patients into 3 groups following the results of the Framingham study that the cardiovascular and all-cause mortality risks for hypertensive patients with ≥75 bpm OPR were higher than <75 bpm, and ≥85 bpm OPR were higher than <75 bpm (Citation16). In general, risks of death from any cause and of non-sudden or sudden death from myocardial infarction were increased in people with heart rate above 75 bpm (Citation17). From the results of NHANS I, the risks of all-cause mortality and death from cardiovascular disease in people with heart rate above 84 bpm was high (Citation18). The changes in the proportion of patients in “sustained hypertension” and “normotension” categorized by OBP and MHSBP at baseline and after 12 months were also evaluated.
Statistical analysis
The target number of patients was determined to detect ADRs. To collect data from more than 100 patients ≥75 years, those with CLD, and those with CKD who had been admitted for at least one year, it was necessary to collect data from 2200 patients from previous cilnidipine post-marketing surveys. We determined that if at least 100 patients were assigned to each group, it would be possible to detect ADRs that occur with a frequency of 3% with 95% confidence. Data are expressed as the mean ± standard deviation for continuous variables and as percentages for discrete variables. The changes in OPR from baseline at 12 months were analyzed by Student’s t-test or paired t-test. The changes in OBP and HBP or OPR at 3, 6, 9, and 12 months were analyzed by Dunnett’s multiple comparison test. Fisher’s exact test was used to examine the differences in proportions. In all tests, P < .05 (two-tailed) was considered significant. All statistical analyses were performed using a statistical software package (SAS, version 9.3, SAS Institute, Cary, NC) in an independent facility (INTAGE Healthcare Inc.).
Results
Subjects of analysis
In total, 2672 patients were enrolled in the survey (). Survey sheets were collected from 2622 patients and were not obtained from 50 patients. The 50 patients were excluded from the safety analysis because there was no information except subject number about these subjects. While analys data for investigating the safety of SPC of Cil/Val, we excluded patients whose survey sheets were not collected (N = 50). Patients who did not visit after the initial visit (N = 41), whom the physicians did not register within 15 days of first prescription (N = 9), and who had other reasons (N = 2) including overlap were also excluded. In addition, 200 patients were excluded from efficacy analysis, because of the absence of baseline BP variables measured in the office or at home.
Figure 1. Breakdown of patient enrollment.
Patient characteristics
The mean age of the patients was 67.6 ± 12.7 years; 53.4% of the patients were men, and the mean BMI was 24.4 ± 3.9 kg/m2. The number of patients aged ≥75 years, with CLD, and with CKD was 814 (31.6%, 814 of 2572 patients), 202 (7.9%, 202 of 2572 patients), and 285 (11.1%, 285 of 2572 patients), respectively (). The largest patient cohort consisted of patients with hypertension for ≥5 years and <10 years (18.3%, 471 of 2572 patients). Regarding complications, 34.3% (883 of 2572 patients) of patients had dyslipidemia and 19.1% (490 of 2572 patients) had diabetes mellitus. Most patients (91.8%, 2361 of 2572 patients) received antihypertensive treatment before enrolling in this survey. The SPC of Cil/Val was not administered to children and pregnant women. The average daily dose was 1.0 ± 0.1 tablet (mean ± SD). The percentage of patients that received SPC of Cil/Val for 12 months was 78.3% (2015 of 2572 patients), and the percentage of patients that received the SPC for less than 3 months was 9.3% (238 of 2572 patients). The number of patients who discontinued the SPC of Cil/Val was 557 at 12 months, including 76 patients whose BP lowering effect was too strong, 16 patients whose hypertension was completely cured, 117 patients whose BP lowering effect was less or there was no BP lowering, 63 patients who did not want to continue receiving the SPC without adverse events, 37 patients with adverse events but no relation with the SPC, 183 patients discontinued to visit clinic or hospital, 4 patients whose reason for discontinuing the SPC was not investigated, and 87 patients with ADRs including overlap.The baseline characteristics of the 2372 patients in whom the efficacy of SPC of Cil/Val was evaluated are shown in Supplementary Table 2. Regarding pre-treatment antihypertensive drugs, the percentage of angiotensin II receptor antagonists and calcium channel antagonists was 55.2% (1309 of 2372 patients) and 66.0% (1565 of 2372 patients), respectively. The percentage of patients who received concomitant antihypertensive drugs was 28.6% (678 of 2372 patients).
Table 1. Patient characteristics.
Safety
In this survey, 97 ADRs were observed, which represented 3.77% of the study subjects (97 of 2572 patients) (). The discontinuation rate of the SPC of Cil/Val due to ADRs was 3.38% (87 of 2572 patients). The main ADRs with more than 5 events were dizziness (0.54%, 14 events in 2572 patients), decrease in blood pressure (0.47%, 12 events in 2572 patients), headache (0.27%, 7 events in 2572 patients), hypotension (0.27%, 7 events in 2572 patients), hot flush (0.19%, 5 events in 2572 patients), and nausea (0.19%, 5 events in 2572 patients) (). Seven serious ADRs occurred in 5 patients, i.e., 2 events of hyperkalemia, 2 events of renal impairment, 1 event of atrial flutter, 1 event of anal fissure, and 1 event of hemorrhoids. Four events in 3 patients, namely 2 events of hyperkalemia and 2 events of renal impairment. Of these 3 patients, the first patient with both hyperkalemia and renal impairment had CKD and high levels of serum potassium and creatinine before initiation of SPC of Cil/Val treatment. The second patient with hyperkalemia had CKD; however, detailed medical information could not be obtained. The third patient with renal impairment had CKD and high levels of serum creatinine before initiation of treatment with SPC of Cil/Val. The patient who had atrial flutter stopped taking the SPC of Cil/Val; nonetheless, atrial flutter did not recur after two separate formulations of cilnidipine 10 mg and valsartan 80 mg were re-administered. Anal fissure and hemorrhoids were observed in one patient, but detailed medical information could not be obtained. The frequency of ADRs was 3.93% (32 of 814 patients) in patients ≥75 years of age, 6.44% (13 of 202 patients) in those with CLD, and 5.26% (15 of 285 patients) in those with CKD. On comparing the frequency of ADRs between patients ≥75 years of age and <75 years, those with and without CLD, and those with and without CKD, no significant difference was observed between the groups (). In these patients, approximately half of the ADRs occurred within the first 3 months of administration of SPC of Cil/Val, and most ADRs were observed at 6 months of treatment. The frequency of ADRs did not increase in a time-dependent manner during long-term observation.
Table 2. Adverse drug reactions.
Table 3. Comparison of adverse drug reactions in patients aged ≥75 years and <75 years, those with and without chronic liver disease, and those with and without chronic kidney disease.
Efficacy
Both office systolic and diastolic BP values significantly decreased after 3 months of treatment and remained low thereafter (P < .01, ). OPR values also significantly decreased at 6, 9, and 12 months after treatment with SPC of Cil/Val (P < .01). There was a significant decrease in OPR from baseline at 12 months in all patients (P < .01, N = 1900). In patients with a baseline OPR ≥75 bpm and <85 bpm (N = 526) and in those with baseline OPR ≥85 bpm (N = 399), the OPR significantly decreased (P < .01, ). In this survey, both OSBP and MHSBP values were obtained in 1031 patients; 14.5% of patients were “normotensive” at baseline; however, this proportion significantly increased to 51.1% after 12 months of treatment with SPC of Cil/Val (P < .01). The proportion of patients with “sustained hypertension” was 61.6% at baseline, which significantly decreased to 18.0% at the end of the survey (P < .01, ). According to the target OBP and HBP values recommended in JSH 2014 (Citation1), the proportion of patients that achieved each target OBP and HBP values were 29.8% and 22.9% at baseline and increased to 69.0% (P < .01) and 58.4% (P < .01) after 12 months of treatment with SPC of Cil/Val, respectively. The proportion of patients that achieved the new target OBP or HBP values recommended in JSH 2019 (Citation2) were 18.7% and 12.1% at baseline and increased to 45.0% (P < .01) or 31.6% (P < .01) after 12 months of treatment with the SPC of Cil/Val, respectively ().
Table 4. Control rates of hypertension according to JSH 2014 or JSH 2019.
Figure 2. Changes in office blood pressure and pulse rate.
Figure 3. Changes in office pulse rate in relation to baseline office pulse rate.
Figure 4. Changes in the percentage of patients categorized by office systolic blood pressure and morning home systolic blood pressure at baseline (a) and after 12 months of treatment (b).
We analyzed the effect of pre-treatment of antihypertensive drugs on the OBP at 12 months after treatment of the SPC of Cil/Val. The OBP of patients without pre-treatment antihypertensive drugs was higher than that of patients with pre-treatment of antihypertensive drugs at baseline. However, there were no significant differences between presence and absence of pre-treatment antihypertensive drugs on OBP at 12 months (Supplementary Table 3). Since we had collected the information on the presence or absence of concomitant antihypertensive drugs during that period, we analyzed the effect of presence or absence of concomitant antihypertensive drugs on OBP. There was almost no difference between presence and absence of concomitant antihypertensive drugs on OBP at 12 months after treatment with the SPC of Cil/Val, and the change of home BP from baseline to 12 months (Supplementary Table 4).
Discussion
This survey focused on the safety and efficacy of SPC of Cil/Val in patients with hypertension in a real-world setting. The number of patients per subgroup (patients ≥75 years of age, those with CLD, and those with CKD) was adequately powered to evaluate the occurrence of ADRs (3%) with 95% confidence. The results showed that only 3.77% of patients experienced ADRs in the intention-to-treat population (N = 2572). Most of the ADRs were considered mild to moderate, and the most commonly reported event was dizziness (0.54%, 14 events in 2572 patients). Dizziness and decrease in blood pressure were not serious ADRs and were resolved or resolving in all patients. Of note, dizziness and decrease in blood pressure are mentioned on the package insert for SPC of Cil/Val. Although five cases of serious ADRs were observed, they did not indicate any new safety issues associated with the SPC of Cil/Val. Hyperkalemia and renal impairment were mentioned on the package insert as serious ADRs. There were no extra safety considerations regarding the safety of the SPC of Cil/Val in patients ≥75 years of age, those with CLD, or those with CKD. In these patients, the occurrence of ADRs did not increase in a time-dependent manner. These results suggest that the SPC of Cil/Val can be used to treat hypertension in patients ≥75 years of age, those with CLD, and those with CKD without any significant long-term clinical problems. Thus, we suggest that the SPC of Cil/Val is generally well tolerated in real-world settings. We have previously reported the incidence rate of adverse reactions due to cilnidipine: 2.54% (59 of 2319 patients) in Japanese hypertensive patients in the post-marketing survey (from October 2008 to September 2010) (Citation19) and 2.59% (69 of 2667 patients) in Japanese post-stroke hypertensive patients (between May 2011 and June 2013) (Citation20). We have also reported that the incidence rate of adverse reactions due to coadministration of cilnidipine and ARBs was 2.50% (73 of 2920 patients) (From February 2003 to July 2004) (Citation15), and the incidence rate in the selected 615 patients who were administered 10 mg cilnidipine and 80 mg valsartan was 3.25% (20 of 615 patents) (Citation21). The safety of the SPC of Cil/Val was at least similar to that reported for other antihypertensive drugs.
Elevated pulse rate (PR) has been reported as a risk factor for cardiovascular events (Citation16,Citation22,Citation23). In this survey, OPR decreased markedly after 6 months of administration of the SPC of Cil/Val in hypertensive patients whose baseline OPR was higher (i.e., those with a baseline OPR ≥85 bpm, P < .01). It has been demonstrated that cilnidipine significantly decreases PR in hypertensive patients with a higher baseline PR by blocking sympathetic nervous system activity; therefore, the action of the SPC of Cil/Val on OPR is considered to depend on the sympatholytic effect of cilnidipine through the inhibition of the N-type calcium channels (Citation19,Citation24,Citation25).
The diagnosis of hypertension is classified by both OBP and HBP in JSH 2014 (Citation1). In this survey, the SPC of Cil/Val increased the percentage of “normotensive” patients from 14.5% to 51.5% and decreased the percentage of “sustained hypertensive” patients from 61.6% to 18.0%. Therefore, it can be concluded that the SPC of Cil/Val can control not only OBP, but also HBP in hypertensive patients in real-world clinical practice. Both proportions of patients achieved the target OBP and HBP values recommended in JSH 2019 (Citation2) after 12 months of treatment with the SPC of Cil/Val. Although a target level for BP control was not stipulated in this survey, this survey was carried out from October 2014 to July 2017, during which time the physicians worked to achieve the BP levels defined in JSH 2014 (Citation1). When the target level for BP was lowered in the new hypertension management guidelines, the BP control rates were understandably lowered as the data that was being reviewed adhered to the old hypertension management guidelines (Citation26,Citation27).
In case of presence or absence of pre-treatment or concomitant antihypertensive drugs, OSBP and office diastolic BP were 133–135 mmHg and 74–76 mmHg at 12 months, respectively. Therefore, we thought that the physicians tried to lower blood pressure to the target BP levels according to JSH 2014.
This survey, nonetheless, has certain limitations. First, this is a non-randomized, open-label, single-arm study that does not allow a comparison between treatment and control groups. However, the observational nature of the post-marketing survey has enabled the collection of real-world data from a naturalistic clinical setting and from a large number of patients. Second, the HBP values may include transcription errors and report bias, because the patients themselves measured HBP. Future studies over a longer duration are necessary to investigate the potential clinical benefits of this SPC on organ protection and the improvement of cardiovascular outcomes in hypertensive patients. Third, we could not know if physicians changed antihypertensive drugs or not during the observation period because we did not collect that information about the change of class of antihypertensive drugs and dose of antihypertensive drugs. However, regardless of presence of pre-treatment antihypertensive drugs, physicians must try to achieve target blood pressure levels by adding antihypertensive drugs.
In conclusion, the findings of the HOPE-Combi survey show that the SPC of Cil/Val is safe and effective for the treatment of blood pressure in hypertensive patients in real-world settings.
Declaration of interest
Kazuomi Kario received scholarship donations from MOCHIDA PHARMACEUTICAL CO., LTD and an honorarium as a medical professional from EA Pharma Co., Ltd. for this survey. Saori Matsuda, Shinobu Nagahama, Yoshiki Kurose and Maki Wakabayashi are employees of EA Pharma Co., Ltd. Hitoshi Sugii, Tsukasa Teshima, and Noriyuki Suzuki are employees of MOCHIDA PHARMACEUTICAL CO., LTD.
Supplemental Material
Download MS Word (36.1 KB)Acknowledgments
We would like to express our deepest gratitude to the physicians who provided valuable data and for their cooperation in conducting the HOPE-Combi survey. We would also like to thank Junko Yamashita, an employee of EA Pharma Co., Ltd., for planning the survey and progress management.
Supplementary material
Supplemental data for this article can be accessed here.
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References
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