This was a national, multicenter, non-interventional, longitudinal product registry on the safety of IA-FDC in the real-life management of hypertension in Lebanon. Twenty-five participating sites were randomly selected from an exhaustive list of physicians who treat patients with hypertension, with a geographical distribution that covers all Lebanese governorates. Eighteen of the participating investigators were cardiologists, three nephrologists, two family physicians, and two endocrinologists. Most of them (18 out of 25) practiced in private clinics, and the rest in hospital settings. Patients were recruited over a 12-month period, from March 30, 2017 until March 31, 2018. Patients attended the baseline visit, and were followed up at the 3-month, the 6-month, and the 9-month visits. This study was approved by all applicable ethics committees/institutional review boards of participating centers.

Male or female adult patients who provided informed consent and who have been treated with IA-FDC for at least three months and at most six months prior to baseline visit were consecutively recruited in this study. The decision to initiate IA-FDC was at the physician's discretion independently of study participation. Patients participating in another clinical trial or with history of allergies or contraindication to any of the IA-FDC product, as well as pregnant or breastfeeding female patients were excluded from the study.

The Enrolled population is constituted by all patients included in the study. The Safety population is constituted by all patients who have taken at least one dose of the study treatment. The Reference population is constituted by all hypertensive patients, fulfilling the eligibility criteria, and who came to the selected sites during the specified study period, and attended the 3 follow up visits after the baseline visit.

At each study visit, patient data were collected on individual paper case report forms, then entered into a database and validated. Collected data included all adverse events (AEs), demographic and socioeconomic profile, vital signs, medical history and specifically hypertension profile, and concomitant medication.

Data analysis was performed under SAS 9.4. Numeric values were summarized as observed valued, mean and standard deviation (SD), minimum and maximum, and two-sided 95% Wald confidence interval (CI) of the mean for all endpoints. Categorical variables were summarized as number of non-missing data, counts and percentages, two-sided 95% CI using Agrest-Coull method for all endpoints. Variables were analyzed according to gender, age categories, and body mass index (BMI) categories. Analysis presented the Odds ratio (OR) between subgroups.

The primary objective of the study was to assess in real-life practice the safety profile of IA-FDC when used to treat hypertension in Lebanon by estimating the frequency, severity and seriousness of AEs. As the primary and secondary criteria were described as rates, a good precision was needed in estimating these percentages. With 600 patients from all over Lebanon, the study would allow the estimation of any prevalence among patients such as prevalence of AEs or certain comorbidities to a margin of error of maximum ±4% using 95% CI.

For statistical tests, the type I error risk was set at 5% (bilateral situation). No adjustment for multiplicity was performed. For inter-group comparison, a Student t-test or a Wilcoxon/Mann–Whitney test was performed, depending on the normality of the data, to test the hypothesis involving quantitative variables. In case of normality in all groups and Student t-test is chosen, a test of equality of variance before a Satterthwaite's correction was applied. The Chi square test or the Fisher's exact test, depending on the expected counts, was used to test the hypothesis involving qualitative variables. To test the differences between baseline and post-baseline values, a paired t-test or a Wilcoxon signed rank test was used depending on the normality of the data. Missing data or unknown responses were not included in the percentages and probabilities associated with tests.

Over a 12-month period, 603 patients were recruited in 25 centers across Lebanon, with 602 included in the safety population and 565 in the reference population (Fig. 1). The reference population included more males (315 [55.75%]). The age of the patients ranged from 22 to 93 years, with an average of 58.3±11.0 years and a median of 58 years. The majority of patients were married (73.81%) and most patients went to school (63.54%) or held a university degree (26.73%). Only 5.49% of the patients reached higher education and 1.77% could not read or write. Most of the patients were covered by health insurance (78.58%) and a fifth was unemployed.

Fig. 1.

Disposition of patients.

(0.14MB).

Weight at baseline ranged from 50.00 to 130.00kg, with a mean of 83.36±12.56kg. Height was available for 502 patients and ranged from 150.00 to 188.00cm with a mean of 170.9±7.5. BMI was therefore computed for 501 patients who had both their weight and height collected at the study visit, and ranged from 19.0 to 44.4kg/m2, with a mean of 28.28±4.09kg/m2. According to the World Health Organization classification, only 96 patients (19.16%) had a BMI within the normal range, and the remaining 405 patients were overweight (53.09%) or obese (27.74%).

Medical history was also described for all patients in the reference population, and 64.78% presented comorbidities, while 49.91% took at least one concomitant medication. Fig. 2 displays comorbidity reported and concomitant medications. Dyslipidemia topped the list with 79.51% of patients with comorbidity suffering from it, while HMG CoA reductase inhibitors were the most prescribed in 67.73% of patients treated with concomitant medications.

Fig. 2.

Medical history of participants. A, main comorbidities reported by patients and B, concomitant medications taken by more than 10% of patients. HMG CoA: 3-hydroxy-3-methylglutaryl-Coenzyme A; OAD: oral anti-diabetic drug.

(0.17MB).

Safety events, their frequency, severity and seriousness were analyzed to describe the safety profile of IA-FDC. Within the safety population, 71 (11.79%) patients reported at least one AE, of which, 65 (91.55%) reported at least one non-serious AE (NSAE), and 6 (8.45%) reported at least one serious AE (SAE). No AE of special interest (AESI) was reported in any of the study patients. One AE led to permanent treatment discontinuation and was classified as non-serious. Moreover, 41 (57.75%) patients reported at least one mild AE, 24 (33.80%) reported at least one moderate AE, and 7 (9.86%) reported at least one severe AE. Percentages of patients reporting AEs are summarized in Table 1.

Treatment-emergent AEs (TEAEs) were experienced by 36 (5.98%, 95% CI [4.33%; 8.19%]) patients of the safety population. A total of 7 SAEs were also reported in 6 (1.00%) patients and none of them was a TEAE. They included a hip fracture, an acute myocardial infarction, one sudden cardiac death, one case of cholelithiasis, one case of Meniere's disease and two cases of rectal hemorrhage. Also, 68 NSAEs were reported in 65 (10.80%) patients, among which 36 were TEAEs and were divided into 33 peripheral edema events, two hypotension events and one tachycardia event.

Subgroup analysis showed that there was no statistically significant effect of patients’ gender, age or BMI on the occurrence of most AEs. Only moderate AEs seemed to be reported more frequently by women (p=0.001). Fig. 3 shows that among patients with mild AEs, significantly more reported AEs were TEAEs, whereas among patients with moderate AEs, significantly more reported AEs were non-TEAEs. Treatment-emergence was not statistically significant when severe AEs were considered.

Fig. 3.

Treatment-emergent adverse events and non-treatment-emergent adverse events in patients presenting mild adverse events compared to those presenting moderate adverse events (*p<0.0001).

(0.06MB).

Patients in the reference population had had hypertension for a maximum of 32.0 years prior to study initiation. In particular, 39.9% of patients were diagnosed with hypertension within the year leading up to study start, 41.9% between one and five years, and 28.2% over five years before study start. The highest systolic BP (SBP) recorded during the last three months before patient enrollment ranged from 110 to 230mmHg with an average of 160.9±21.5mmHg. The highest diastolic BP (DBP) recorded during the same period ranged from 60 to 120mmHg with an average of 93.0±10.4mmHg. Fig. 4A displays the distribution among hypertension grades of the 556 patients for whom BP measurements were available within three months prior to study entry. Only around 15% of them had controlled BP, more than 70% of patients reported a family history of hypertension, and around half of them applied lifestyle measures to reduce their BP, mainly through diet, physical activity, and smoking cessation.

Fig. 4.

Patient hypertension status. Data were analyzed for patients in the reference population. Percentage of patients with controlled BP and distributed among hypertension grades prior to study entry (A) and at the baseline visit (B); number of patients reporting the main hypertension-related complications (C). CAD: coronary artery disease; LVH: left ventricular hypertrophy.

(0.14MB).

At study entry (baseline visit), patients had been treated with IA-FDC for at least 3 months, with 369 (65.43%) having their BP controlled (Fig. 4B) and 168 (29.73%) patients were taking at least one additional antihypertensive medication. Beta blocking agents were by far the most prescribed medication (around 60%), followed by diuretics (around 30%). At least one complication due to hypertension was reported by 242 (42.83%) patients. These complications were mostly cardiovascular (90.50%) and microvascular (35.54%). Fig. 4C displays ongoing hypertension complications reported by more than 10% of patients at study entry, left ventricular hypertrophy topping the list, followed by coronary artery disease.

The absolute majority of the reference population (99.47% of patients) was taking four doses of IA-FDC (150/5mg; 150/10mg; 300/5mg; 300/10mg) and the treatment was initiated for an average of 3.86±0.85 months prior to baseline visit. Around 11.68% of patients had an IA-FDC escalation at the baseline visit, but more than 95% of the patients had no change in their IA-FDC doses during the 3-month, 6-month, and 9-month follow up visits.

DBP and SBP values were recorded for patients on every study visit. Fig. 5 displays the change in these values from baseline through all follow up visits. Average SBP was 136.0±17.3mmHg at baseline and 125.0±7.8mmHg at the 9-month follow up visit, showing a significant decrease of 11.0±18.8mmHg (p<0.001). Similarly, average DBP was 81.7±8.5mmHg at baseline and 77.0±5.7mmHg, showing a significant decrease of 4.60±9.67mmHg (p<0.001). Of note, the decrease in SBP and DBP was significant when comparing the values at baseline to those at any of the study visits. Around 80% of patients for whom BP values were available at all study visits, achieved their target BP within 3 months post-baseline, 13.27% within 6 months, and 7.10% within 9 months. At the end of the study, 86.19% of the patients had their BP controlled.

Fig. 5.

Changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline across study visits. *, p<0.001 (calculated using the Wilcoxon signed rank test).

(0.07MB).

In an attempt to evaluate how SBP and DBP responded to the different doses across study visits, total BP measurements were recorded and reported for the four different IA-FDC doses. Values came as follow: for the 150/5mg dose (N=518), SBP was 128.9±12.6mmHg and DBP was 78.4±7.5mmHg; for the 150/10mg does (N=4), SBP was 135.0±23.8mmHg and DBP was 80.0±14.1mmHg; for the 300/5mg does (N=1240), SBP was 128.2±11.4mmHg and DBP was 78.4±6.5mmHg; and for the 300/10mg does (N=494), SBP was 129.3±13.2mmHg and DBP was 79.1±6.9mmHg. These differences were not statistically significant.

There was also a significant and sequential decrease in the average heart rate from the baseline (76.1±8.4bpm) to the 9-month visit (74.3±6.9bpm) (p<0.001) and in the average weight from the baseline (83.36±12.56kg) to the 9-month visit (81.18±11.48kg) (p<0.001). This is of utmost important since at baseline, more than half of the patients were physically inactive (61.24%), smokers (57.52%), following an unhealthy diet (55.93%) and under stress (52.57%).

Subgroup analysis showed that patients presenting IA-FDC TEAEs (N=34) had a significantly higher weight (88.14±14.91kg) than those presenting AEs not related to IA-FDC (N=33; 6.14±14.29kg) (p=0.001). They were also diagnosed with hypertension for a significantly longer period (5.85±5.80 years versus 2.00±2.66 years, p<0.001). Moreover, patients having taken higher doses of IA-FDC prior to the study (p<0.001), at the baseline visit (p=0.04) and at the 3-month visit (p=0.03) had significantly more TEAEs. In particular, peripheral edema seemed to be more significantly associated with higher doses of amlodipine, namely IA-FDC 150/10mg and 300/10mg compared to IA-FDC 150/5mg and 300/5mg (p=0.001). None of the other AEs had a significantly different occurrence in the doses subgroups.