Hypertension is a major public health problem due to its high prevalence and close relationship with cardiovascular events. But, current blood pressure (BP) control rates are still far from the target of 50% proposed for the year 2010 (USHHS 2006). It has been demonstrated in recent clinical trials that BP control can only be achieved with two or more antihypertensive drugs in most cases (Cushman et al. 2002; ESH 2003). The poor control of hypertension may be partially due to the low treatment compliance of the patients. Some factors that have been involved in this poor compliance are adverse events related to antihypertensive drugs, lifelong treatment, and polymedication (Osterberg and Blaschke 2005). Calcium channel blockers (CCB) are widely used drugs for the treatment of hypertension. Lercanidipine is a highly lipohilic third generation dihydropyridine (DHP) (Bang et al. 2003). Its antihypertensive effect results from peripheral vasodilation and decreased total peripheral resistance (Meredith 1999). This drug has a slow onset of action due to its high lipophilicity and its partitioning into the lipid bilayer of cell membranes, followed by diffusion to the receptor binding site, that helps to avoid reflex tachycardia associated with other DHP, such as nifedipine (Ambrosioni and Circo 1997; Meredith 1999). Its efficacy has been evaluated in noncomparative (Barrios et al. 2002; Viviani 2002; Barrios et al. 2006a; Barrios et al. 2006b) and comparative studies (Agrawal et al. 2006; James et al. 2002; Millar-Craig et al. 2003;). In most trials the starting dose was 10 mg/day. Lercanidipine is generally well tolerated during monotherapy in patients with mild-to-moderate hypertension (Barrios et al. 2002; Borghi et al. 2003). Because in older population the occurrence of side effects is more likely, the use of well-tolerated drugs is particularly important in these patients. Lercanidipine has been shown to be safe even in the elderly (Barbagallo and Barbagallo Sangiorgi 2000; Leonetti et al. 2002).
DHP-related adverse events are generally associated with vasodilation and include headache, dizziness, flushing, or edema (Leonetti 1999). In previous studies lercanidipine has been compared to other DHP such as nitrendipine (Rengo and Romis 1997), nifedipine SR (Policicchio et al. 1997), and nifedipine gastrointestinal therapeutic system (GITS) (Cherubini et al. 2003; Romito et al. 2003) with a lower incidence of adverse events favoring lercanidipine. Nonetheless, this information is derived from clinical trials with commonly strict inclusion and exclusion criteria with less information available from “real world” clinical settings.
The main objective of the TOLERANCE (TOlerabilidad de LERcanidipino 20 mg frente a Amlodipino y Nifedipino en CondicionEs normales de uso) study was to compare the tolerability, with special emphasis on vasodilation-related adverse reactions, of high doses of lercanidipine with other DHP (amlodipine and nifedipine GITS) also given at daily high doses. The study was performed in Primary Care setting in conditions of common clinical practice.
It was an observational, cross-sectional and multicenter study performed in Primary Care Centers from all around Spain. The study population were outpatients aged ≥ 18 years with essential hypertension who had been treated at least for 1 month with lercanidipine, amlodipine, or nifedipine GITS at low doses (10, 5, and 30 mg daily, respectively) and who were titrated to higher doses of the same drugs (20, 10, and 60 mg, respectively) in a 2:1:1 design because of a BP below target. They should have been treated with these high doses during at least 1 month before entering the study (Figure 1). Patients with heart failure were excluded. Subjects had to give their written informed consent to participate in the study. The study was evaluated and approved by the Ethics Committee of the Ramon y Cajal University hospital in Madrid.
The main objective of the study was to determine the rates of adverse events linked to vasodilation in patients treated with lercanidipine 20 mg. This prevalence was compared with that of a group of subjects treated with amlodipine or nifedipine GITS at high doses. Other objectives were: (1) Evaluate the frequency of the commonest adverse reactions associated to lercanidipine (defined as those adverse events reported in registration clinical trials with a frequency > 5%); (2) Determine the frequency of adverse reactions spontaneously notified by the patient (answering the question “have you noticed any discomfort related to the drug?”); (3) Evaluate the percentage of patients with an adequate BP in both groups; (4) Compare the patient's therapeutic compliance with every drug.
Adverse reactions were spontaneously reported by the patient or elicited using a 16-item checklist similar to the one used in the COHORT trial (Leonetti et al. 2002) that included those symptoms considered related to vasodilation and the most commonly adverse events reported during registration trials (see Appendix 1). Adequate BP control was defined as <140/90 mmHg in general population and <130/80 mmHg in people with diabetes (ADA 2005; ESH 2003). Since this study was aimed to reflect clinical practice, when BP control was not attained, the investigators could freely add more antihypertensive medication.
BP was measured with a standard mercury sphygmomanometer. Two measurements were taken, both in the sitting position and in the same arm with a 5-minute interval, and the average was used as the reference value. Patients underwent a complete physical examination, and they should have a complete blood test (hematology and biochemistry with a lipid profile) performed in the last three months before entering the study.
Treatment compliance was assessed through the Haynes-Sackett test (Sackett et al. 1991).
The study sample calculation was based on the results of two previous studies (Leonetti et al. 2002; Romito et al. 2003). Based on the different proportions of edema detected in the first study (Leonetti et al. 2002) (9% lercanidipine vs. 19% amlodipine) and with the presence of an active control group with Nifedipine GITS, if we wanted to detect that difference we had to include a total of 650 patients (power = 90%, α= 0.05). No dropouts were expected, as it was an observational study.
The primary variable of the study was evaluated through the frequency of ankle edema and other vasodilation-related adverse events according to the checklist used in the study. Secondary endpoints were frequency of spontaneously adverse events notified by the patient, rates of BP control, and percentage of patients classified as good compliers according to the Haynes-Sacket test. Continuous variables were averaged and expressed as means ± standard deviation. Categorical items were expressed as percent frequency. 95% confidence intervals were provided when necessary. Differences between means of different parameters were compared by the Student t-test. Differences between percentages were compared with the Fisher's exact test. Categorical data were also analyzed with this test. A P-value < 0.05 was used as the level of statistical significance.
Computations for the statistical method were performed with the use of the SAS system. A logistic regression analysis was performed to determine what factors could influence the incidence of adverse events related to vasodilation (dependent variable). Clinical characteristics of study population, cardiovascular risk factors, target organ damage, associated clinical conditions, antihypertensive treatments, concomitant treatments, and biochemical parameters were included as independent variables in the logistic regression analysis.
A total of 656 consecutive patients were included in the study. The number of evaluable subjects was 650 (99.1%) of whom 446 (68.6%) were taking lercanidipine and 204 (31.4%) amlodipine or nifedipine GITS (n= 113 and 91 respectively). Mean follow-up was 3.6 months. The clinical characteristics of the study population are shown in Table 1. The changes in BP and heart rate values during the study are shown in Table 2. The percentage of patients with an adequate BP control was 46.4% in the lercanidipine group versus 38.1% in the amlodipine/nifedipine group (P= NS). Concomitant antihypertensive therapy in both groups is shown in Table 3. There were more patients in the amlodipine/nifedipine group with concomitant antihypertensive medication than in the lercanidipine group (49%[42.1–55.9] vs. 38.3%[33.8–42.8] respectively, P= 0.013). Regarding the type of concomitant antihypertensive drugs, the only difference was a higher rate of angiotensin converting enzyme (ACE) inhibitors use in the amlodipine/nifedipine group (17.7 vs. 9%; P= 0.002). There were no significant differences between both groups in biochemical parameters as shown in Table 4.
|Global (n= 650)||Lercanidipine (n= 446)||Amlodipine/nifedipine (n= 204)||P|
|Age (years)||64.4 (11.1)||64.1 (10.9)||65.3 (11.4)||NS|
|BMI (kg/m2)||28.4 (4.3)||28.5 (4.3)||28 (4.2)||NS|
|Waist circumference (cm)||96.7 (15.5)||97 (15.7)||95.9 (15)||NS|
|Time since diagnosis (months)||63.7 (65.4)||62.2 (66)||66.9 (64.2)||NS|
|Family history of hypertension||56.7%||54.9%||60.4%||NS|
|Global (n= 650)||Lercanidipine (n= 446)||Amlodipine/nifedipine* (n= 204)|
|SBP (low dose) mmHg||155.5 (13)||155.1 (13.8)||156.4 (11)|
|DBP (low dose) mmHg||90.3 (8.3)||90.4 (8.4)||90.1 (8.2)|
|HR (low dose) b.p.m.||78.3 (8,7)||78 (8.7)||78 (8.7)|
|SBP (high dose) mmHg||142.7 (12.4)||142.3 (12.2)||143.6 (12.7)|
|DBP (high dose) mmHg||82.3 (7.7)||82 (7.6)||83 (8)|
|HR (high dose) b.p.m.||76.5 (8.3)||76.4 (8.4)||76.7 (8.2)|
|Global (n= 650)||Lercanidipine (n= 446)||Amlodipine/nifedipine (n= 204)||p|
|Global (n= 650)||Lercanidipine (n= 446)||Amlodipine/nifedipine (n= 204)||P|
|Glucose (mg/dL)||112 (37.1)||113.1 (41.4)||109.5 (25.7)||NS|
|Creatinine (mg/dL)||1.0 (0.4)||1.0 (0.4)||1.0 (0.3)||NS|
|Sodium (mEq/L)||140 (4.7)||139.2 (5.0)||140.2 (4.1)||NS|
|Potassium (mEq/L)||4.3 (0.5)||4.3 (0.5)||4.3 (0.5)||NS|
|Urate (mg/dL)||5.8 (1.4)||5.8 (1.4)||5.9 (1.5)||NS|
|Cholesterol (mg/dL)||216 (36.9)||217 (36.4)||214 (38)||NS|
|c-HDL (mg/dL)||53.7 (17)||54.6 (18)||51.9 (14.8)||NS|
|c-LDL (mg/dL)||136.4 (31.2)||136.5 (31.1)||136.2 (31.4)||NS|
|Triglycerides (mg/dL)||150.3 (68.9)||149.3 (58.2)||152.4 (87.8)||NS|
Rates of signs and symptoms related to vasodilation were significantly higher (P < 0.001) in the amlodipine/nifedipine group (76.8%, CI 95%[70.7;82.9]) vs. lercanidipine group (60.8%, [56.1;65.5]) when the drugs were given at high doses. Corresponding figures for low doses were 41.2%[36.3;46.1] for lercanidipine and 58.8%[51.5;66.1] for amlodipine/nifedipine, the difference was statistically significant (P < 0.001). The difference in prevalence of vasodilation-related adverse reactions between high and low doses in every group was also significant (60.8 vs. 41.2% for lercanidipine and 76.8 vs. 58.8% for amlodipine/nifedipine, both P < 0.001). Table 5 shows the distribution between groups of drug related signs and symptoms according to the checklist.
|Signs/symptoms||Global (%) (n= 650)||Lercanidipine (%) (n= 446)||Amlodipine/nifedipine (%) (n= 204)||P-value|
Classification of the severity of adverse reactions was as follows: 74.5%[69.1–79.9] mild, 22.7%[17.5–27.9] moderate, and 2.8%[0.7–4.9] severe in the lercanidipine group versus 64%[56–72] mild, 32.4%[24.6–40.2] moderate, and 3.6%[0.5–6.7] severe in the amlodipine/nifedipine group. Differences between groups were statistically significant for mild (P= 0.035) and moderate adverse events (P= 0.040), but not for severe ones. With regard to adverse events spontaneously notified by the patients, there were no statistically significant differences between both groups of DHP-treated patients. Around 2.7% of patients from lercanidipine group and 6.1% from amlodipine/nifedipine group dropped out during the first month of the high dose treatment (P= NS).
According to the Haynes-Sackett test, the percentage of patients considered good compliers was similar in both groups (93.9% lercanidipine vs. 93.7% in amlodipine/nifedipine, P= NS). Concerning the changes in antihypertensive treatment made by the investigators, in 91.2% of patients in the lercanidipine group the treatment was maintained, whereas in the amlodipine/nifedipine group only 56.1% did not change their treatment regimen (P < 0.001). Table 6 shows the most frequent changes in the therapeutic regimen made by the investigators. The most frequent modification performed in lercanidipine group was the addition of a new agent (75.7%), while in amlodipine/nifedipine group the change to other CCB (68.3%).
|Global N= 119||Lercanidipine N= 37||Amlodipine/ nifedipine N= 82||P-value|
|Add a new agent||44.5%||75.7%||30.5%||<0.001|
|Reduce dose of CCB||16%||27%||11%||0.033|
|Withdraw the CCB||5%||2.7%||6.1%||NS|
|Change of CCB||47.1%||-||68.3%||<0.001|
A logistic regression model was performed to check which factors could influence the appearance of adverse events related to vasodilation. The following variables were found to be significant: male sex (Odds ratio 2.072, CI 95%[1.395–3.077]), sedentary life (1.608, [1.085–2.384]), antecedents of cardiac (6.102 [2.668–13.954]), or gastrointestinal diseases (1.965 [1.157–3.335]). Patients in the lercanidipine group had a lower risk of having these adverse reactions (odds ratio 0.436 [0.278–0.684]).