Study Population Characteristics
A total of 1814 patients with essential hypertension were enrolled at 614 study sites in Germany. The median enrollment was three patients per study center (489 centers, 79.6% of centers) and the amount ranged from 1 to 12 patients per center.
Mean duration of observation was 3.3 months (± 0.9, median 3.2, maximum up to 12), the most frequent duration of observation was 3–4 months (901 patients, 51.5% of all patients with data on duration of observation).
Eleven patients only came to the enrollment visit and were never followed up, while another 33 patients were lost to follow-up or have incomplete data, so, in total, data of 44 patients (2.4%) were not available for analysis. Complete data on all visits, baseline, control and final examinations, were available for 1720 patients (94.8% of all patients) for statistical analysis; using the LOCF-method, where–when baseline values exist and at least one follow-up measurement—missing values in the course of the study are replaced by the last actual observation), we have complete data for analysis of baseline and end point measurements in 1770 patients (97.6% of total enrolled).
Patient Characteristics
Of the total study population, 54% were male (see also Table 1). Patients’ mean age was 60 (± 13.4, median 60) years. Patients were predominantly between 50 and 60 years (28% of patients) and between 60 and 70 years (26.8%) old. More than 80% of all patients where either overweight (BMI > 25 and < 30 kg/m2, 46.8%) or obese (BMI > 30 kg/m2, 33.8% of patients), whereas 18.7% were of normal weight (and 0.7% underweight, BMI < 18.5 kg/m2). Laboratory values at baseline visit are shown in Table 2.
Table 1 Patient baseline characteristics
Table 2 Baseline laboratory values of patient population
In the total study population, 88.0% of patients had concomitant risk factors and/or disease, the most common being dyslipidemia (52.8%), obesity (33.9%), tobacco use (33.0%) and diabetes mellitus (20.8%). At study entry, most patients had uncontrolled hypertension ESH/ESC Grades 1–3 (96.5%). Independent of the ESH/ESC grade, 16.1% of all patients had isolated systolic hypertension (ISH).
Patients’ Treatment Status at Baseline
A major focus of the present study was to evaluate the effects of perindopril/amlodipine in untreated patients versus previously treated patients who required a change in antihypertensive medication. Therefore, patients were also stratified according to treatment status at baseline.
Table 1 shows the baseline characteristics of these subgroups. Of the 1770 patients, 803 (45.4%) were previously untreated, whereas 967 (54.6%) were previously on antihypertensive treatment. The mean age was 62.8 ± 12.8 years in the subgroup of previously treated patients and 56.6 ± 13.3 years in the untreated population. Baseline values of blood pressure and heart rate in patients with and without previous antihypertensive therapy were in a similar range—the previously treated group had a systolic blood pressure (SBP) of 161.9 ± 14.4 mmHg, diastolic blood pressure (DBP) of 94.2 ± 9.2 mmHg and a heart rate of 76.7/min ± 10.0; treatment-naive patients had a SBP of 165.7 ± 15.1 mmHg, a DBP of 96.8 ± 9.4 mmHg and a heart rate of 78/min ± 10.1 (differences not significant; Table 2).
In the previously treated subgroup (n = 980 patients), most patients received one antihypertensive drug at study entry (n = 511; 52.1%), while 32.0% received two drugs (n = 314) and 11.6% received three drugs (n = 114) (Fig. 1a). The most frequently preexisting medication consisted of ACE inhibitors (58.3%), betablockers (33.0%), calcium channel blockers (25.1%), AT1 receptor blockers (19.9%), and thiazides/thiazide analogues (18.9%) (Fig. 1b).
Dosing of Perindopril/Amlodipine in the Outpatient Setting: Most Patients Received 3.5 mg/2.5 mg Fixed Combination
At study entry, 97.7% of patients received perindopril/amlodipine at a daily dose of 3.5/2.5 mg, and 47.9% of patients remained on this dose during the course of the study. Dose increases to 7/5 mg perindopril/amlodipine occurred in 28.5% of patients after the first examination, remaining unchanged until the final visit. The mean time until dose increase was 32.9 ± 11.8 days.
Reasons for Medication Change to Perindopril/Amlodipine SPC
The most common reasons given by treating physicians for switching patients on antihypertensive medication to perindopril/amlodipine SPC were insufficient blood pressure control (81.0%), intolerability (15.2%) or non-adherence to the previous medication (12.1%).
Coexisting Medications
Co-medications were checked at each visit. During the course of the non-interventional study, most of the patients had no other antihypertensive medication (68.5%; n = 1242/1814). The most common concomitant antihypertensive treatments were betablockers (n = 403, 22.2%), loop diuretics (n = 137, 7.6%), thiazides (n = 108, 6.0%), AT1-receptor antagonists (n = 35, 1.9%), alpha blockers (n = 34, 1.9%), potassium-sparing diuretics (n = 24, 1.3%) and calcium channel blockers (n = 24, 1.3%). A betablocker was newly commenced during our observation in 42 patients (2.3%), a loop diuretic in 10 patients (0.6%), a thiazide in 23 patients (1.3%).
Other co-medications were statins (n = 482, 26.6%), antiplatelet drugs (n = 212, 11.7%), oral antidiabetics (n = 206, 11.4%), Uricosurics/antigout preparations (n = 79, 4.3%), insulin (n = 63, 3.5%) and other anticoagulants (n = 53, 2.9%). A statin was initiated during our observation period in 24 patients (1.3%) and a dose increase occurred in 12 patients (0.7%).
Blood Pressure Effects of Perindopril/Amlodipine
In the total study population, 1720 patients completed the 3 months follow-up and an additional 50 patients were seen at least for one additional control visit. Overall, office SBP decreased from a mean value of 163.7 ± 14.8 mmHg at baseline to 133.6 ± 11.6 mmHg at final examination (LOCF, n = 1770). Office DBP decreased from 95.4 ± 9.4 to 80.3 ± 7.7 mmHg. The mean difference was 30.1 ± 16.3/15.1 ± 10.3 mmHg (p < 0.0001 vs. baseline for SBP and DBP). Similar reductions in blood pressure occured in home blood pressure measurements in a subset of patients (Fig. 2a).
A statistically significant reduction in office blood pressure was documented as early as visit 2 (− 20.3 ± 14.8/− 9.8 ± 9.7 mmHg; p < 0.0001). In fact, the highest reduction in blood pressure occurred within the first 4 weeks of treatment (Fig. 2b). The effects on blood pressure were accompanied by a significant decrease in heart rate from 77.3 ± 10.1 to 72.7 ± 7.4 bpm (p < 0.0001) (Fig. 2b).
Results of ABPM were available in some patients at the discretion of the treating physician (Fig. 2c). Mean daytime SBP/DBP decreased significantly from 157.8 ± 13.2/92.7 ± 9.5 to 138.0 ± 12.4/82.4 ± 8.8 mmHg at the last observation (− 19.8/− 10.3 mmHg; p < 0.0001 vs. baseline for SBP and DBP, n = 178). Mean nighttime 24 h blood pressure (n = 175) was reduced by 17.2/9.0 mmHg (p < 0.0001 vs. baseline) from 141.8 ± 14.3/83.5 ± 10.6 to 124.6 ± 13.6/74.5 ± 9.7 mmHg. Mean 24 h BP (n = 167) was reduced from 150.6 ± 12.6/88.9 ± 8.8 to 132.4 ± 11.9/79.4 ± 8.5 mmHg (p < 0.0001).
In the subgroup of patients with previous antihypertensive treatment, systolic blood pressure decreased significantly from 161.9 ± 14.4 to 134.1 ± 11.9 mmHg and diastolic blood pressure from 94.2 ± 9.2 to 80.4 ± 7.4 mmHg at the final examination (− 27.8/− 13.9; p < 0.0001 vs. baseline) (Fig. 3a). This was comparable to the blood pressure reduction in previously untreated patients (mean difference: − 32.8/− 13.9 mmHg; p < 0.0001 vs. baseline, Fig. 3a).
Furthermore, patient age did not influence blood pressure response. In the subgroup of patients < 65 years of age, systolic blood pressure decreased significantly (mean difference: − 30.6/− 16.2 mmHg; p < 0.0001 vs. baseline, n = 1133) (Fig. 3b). A comparable decrease was observed in patients 65 years and older (mean difference: − 29.1/− 13.0 mmHg; p < 0.0001 vs. baseline, n = 636) (Fig. 3b).
Blood Pressure Control with Perindopril/Amlodipine
Patients whose blood pressure values were > 140/90 mmHg at the beginning of the study, and who reached the office blood pressure target of < 140/90 mmHg, were classified as controlled. In the total study population, more than two-thirds of the patients reached this goal (69.1%) (Fig. 4a). This effect remained stable in subgroup analyses: The control rate in previously treated hypertensive patients was 68.1% (n = 645/947), comparable to the effect in previously untreated hypertensive patients (70.3%; n = 560/797). Comparable results were also documented in patients with hypertension aged below 65 years (n = 1120) and patients ≥ 65 years (n = 623). At final examination, 791 patients < 65 years (70.6%) and 413 patients ≥ 65 years (66.3%) achieved blood pressure values < 140/90 mmHg (Fig. 4a).
Treatment Response According to Hypertension Severity
At study entry, 21.3% of patients (n = 377) had grade 3 hypertension, 51.1% (n = 905) grade 2 hypertension and 26.1% (n = 462) grade 1 hypertension according to the ESH/ESC guidelines [2] (Fig. 4b). At the final examination, 69.1% (n = 1223) of 1770 patients had controlled hypertension with normal or high normal blood pressure values, while 25.7% (n = 455) patients ended the study with grade 1 hypertension and only 3.8% (n = 68) and 1.4% (n = 24) had grade 2 and 3 hypertension at the end of the study, respectively (Fig. 4b).
When we followed-up the ESC/ESH grade subgroups, of the 426 patients entering the trial with grade 1 hypertension, 86.2% (n = 367) had controlled blood pressure at the end of the trial period. The majority of patients entered the study with grade 2 or 3 hypertension (n = 1282); of these, 65.4% (n = 838) had controlled hypertension at the end of the study period and an additional 28.6% (n = 367) had grade 1 hypertension, showing an improvement in blood pressure (as by the lower hypertension group at study end) in 94% of patients (n = 873) in this group.
Treatment Response in Patients with Isolated Systolic Hypertension
Isolated systolic hypertension (ISH) is associated with increased morbidity and mortality [16]. In our study, 16.1% of all patients (n = 284) entered it with ISH, of whom most patients had ESH/ESC grade 1 (n = 142) or grade 2 (n = 116) (Fig. 4c). At the end of the study, 18.3% (n = 323) of patients had ISH, of whom most had grade 1 hypertension (n = 301) (Fig. 4d). At first glance, ISH may look like a stable population in our dataset. However, analysis of hypertension subgroup tracking showed that the hypertension subtype changed: among the 284 patients entering the study with isolated systolic hypertension, 67.6% (n = 192) had controlled blood pressure at the final examination (Fig. 4c). In contrast, among the 323 patients with ISH at the end of the study, 74.9% had initially presented with systolic/diastolic hypertension (Fig. 4d).
Treatment Adherence Before and After Perindopril/Amlodipine SPC
Adherence to antihypertensive medication, as assessed by the Hill-Bone Medication Adherence scale, was measured at baseline in previously treated patients and in all patients at the final visit (Fig. 5). At baseline, 939 of 980 patients answered the questionnaire; perfect adherence was defined as answering all nine items of the Hill-Bone scale [15] with “none of the time”. Most of the patients with uncontrolled hypertension under treatment showed no perfect adherence (745/939, 79.3%), and only 20.6% were assessed to be perfectly adherent to previous antihypertensive medication [15] (Fig. 5, black bar).
At the final visit, 47.2% of all patients (791 out of 1676) showed perfect adherence to treatment with perindopril/amlodipine. In previously treated patients, adherence increased statistically significantly from 20.6% (n = 185/897) before the study to 43.4% (n = 391/897) at the final visit (p < 0.0001; Fig. 5). In the subgroup of patients without prior antihypertensive treatment, 51.7% (n = 395/764) showed perfect adherence to the study medication.
Safety and Tolerability of Perindopril/Amlodipine SPC
Altogether, 140 ADRs were reported for 88 patients (4.9% of the total population), mostly drug ineffectiveness (n = 19; 1.1%), cough (n = 17; 0.9%), and dizziness (n = 8; 0.4%). Outcome of the ADR was reported to be recovered for 135 events in 83 patients, not recovered for 4 patients (0.2%), and fatal for one event in 1 patient with a hypertensive crisis. The majority of 130 ADR in 80 patients were assessed as non-serious. Seriousness was confirmed for ADR in 8 patients (0.4%). Premature termination of treatment with perindopril/amlodipine was documented in 120 patients (6.6%). The most common reasons for premature termination were AE/ADR in 40 patients (33.3% of patients with premature termination) and lack of compliance in 32 patients (26.7%). In nearly all patients, the tolerability of perindopril/amlodipine was rated by the treating physician as “very good” (n = 1308/1724; 75.9%) or “good” (n = 392/1724; 22.7%).