This multi-institutional retrospective study is the first study to evaluate the mid-term efficacy and safety of FDC versus free combination of amlodipine and atorvastatin in patients with concomitant hypertension and hypercholesterolemia. During the 30-month follow-up period, we found no significant difference in the composite CV outcome among the three study groups. FDC of amlodipine 5 mg and atorvastatin 20 mg resulted in a greater reduction in LDL-C than the other two regimens but the HbA1c level was not significantly different.
In our previous study, we demonstrated that FDC regimen of amlodipine and atorvastatin improved composite CV outcomes compared to FEC of the same medications in patients with newly diagnosed hypertension and dyslipidemia during a 5-year follow-up period . In that study, the medication adherence as assessed by PDC was better in the FDC than in the FEC group (0.49 ± 0.26 versus 0.32 ± 0.3, P < 0.001), and this may explain the results. However, based on the nature of the large administrative NHIRD, the major limitations of the study were a lack of possible confounding variables and efficacy parameters including BP and LDL-C changes. In the current study, we analyzed the efficacy and safety of FDC of amlodipine and atorvastatin by using data from the CGRD, a real-world, multi-institutional, standardized EMR database. In all previous studies, drug compliance with FDC is always better than free combination, which is the main explanation for the beneficial clinical effects of FDC [7, 9–11, 13, 14, 23]. However, the medication adherence as assessed by PDC in the current study was not significantly different among the three study groups, which may be related to the stricter study criteria compared to previous studies that we excluded patients who switched drugs or received the study medications for less than 2 months within 3 months after the index date. Subsequently, the remaining patients, especially those in the free combination group, may have had better drug compliance and tolerability which may explain the comparable medication adherence between the FDC and free combination groups in the present study. Moreover, the follow-up period and patient number were relatively limited that may have further resulted in the similar composite CV outcome among the three study groups.
In previous studies, different dosages of FDC amlodipine/atorvastatin have been administered and titrated to improve BP and lipid control [16, 20–22]. The JEWEL program, which included JEWEL 1 conducted in the United Kingdom and Canada and JEWEL 2 conducted in European countries, was an international open-label study which assessed the efficacy and safety of FDC amlodipine/atorvastatin in attaining BP and lipid targets recommended by country-specific guidelines . Eight dosages of amlodipine/atorvastatin (5/10 to 10/80 mg) were titrated, and 62.9% of the patients in JEWEL 1 and 50.6% of the patients in JEWEL 2 achieved both country-specific BP and LDL-C goals. At the end of the study, the average dosages were 7.3/26.8 mg in JEWEL 1 and 6.7/24.1 mg in JEWEL 2 during a 16-week follow-up period. Similarly, the Gemini and Gemini-AALA studies were also open-label studies conducted in the United States and internationally (Australia, Asia, Latin America, Africa/Middle East), respectively, to evaluate the achievement of BP and lipid goals by titrating different dosages of amlodipine/atorvastatin FDC [20, 21]. After 14 weeks, 57.7% of the patients in Gemini and 55.2% of the patients in Gemini-AALA had achieved both their BP and LDL-C goals. The mean dosages at the end point were 7.1/26.2 mg and 7.1/19.7 mg, respectively. In African Americans, Flack et al reported that different dosages of amlodipine/atorvastatin FDC in addition to lifestyle modification improved the attainment of BP and cholesterol goals . After a 20-week follow-up period, 48.3% of the patients reached both their BP and LDL-C goals, and the mean received dose of amlodipine/atorvastatin was 8.2/26.4 mg at the final visit. In the current study, the patients in the Fixed 5/20 group had a significantly lower LDL-C level than those in the lower dose Fixed 5/10 and Free 5/10 groups, and the amlodipine/atorvastatin 5/20 dosage was closer to the mean dosages of the aforementioned studies, which may explain the better attainment of both BP and lipid goals in our patients. Interestingly, even under the titration design of the aforementioned studies, approximately half of the patients were started on the lowest amlodipine 5 mg/atorvastatin 10 mg FDC dosage, and about 30-60% of these patients were not up-titrated. Current guidelines recommend that the initial dosage of statins should be of moderate intensity [28–30], and it is thus reasonable to first prescribe or early up-titrate to Fixed 5/20 rather than Fixed 5/10 or Free 5/10 in order to achieve better BP and LDL-C control concomitantly.
The risk of NODM with statin therapy has been shown to be positively correlated with the strength of the statins , with a reported overall risk of 9% . In the current study, we also found that the risk of reported NODM was highest in the Fixed 5/20 group and lowest in the Free 5/10 group, and this may be explained by the different strengths of the statins. However, there were no significant differences among the three study groups with regards to HbA1c level during follow-up. The reason for this discrepancy may be multifactorial, such as the different diagnostic criteria for diabetes among physicians, not routinely checking HbA1c level in all patients or by chance. On the other hand, statin-associated liver toxicity is well established, however there are very few reports of liver failure directly attributed to statins [33, 34]. In the current study, we also found an increased risk of ALT elevation in the higher strength statin (Fixed 5/20) group. However, it should be emphasized that the beneficial effects of statins on CVD outweigh the risk of NODM development or mild liver function abnormalities, and therefore adequate dosages of statin should be prescribed if indicated to improve CV outcomes. Myopathy, myalgia and fatigue are also possible adverse effects of statin but it was not routinely examined or reported in our database.
Adequate BP and LDL-C control are recommended by clinical guidelines both in primary and secondary CVD prevention [29, 35, 36]. In our previous study, we only demonstrated the beneficial effect of reducing major adverse cardiovascular events with FDC of amlodipine/atorvastatin in the primary prevention setting . In the present study, we further analyzed the differences in efficacy among three study groups with regards to primary and secondary CVD prevention, and the results were comparable in composite CV outcome. The major adverse cardiovascular event rates were not significantly different among the three study groups both in primary and secondary prevention, which may be due to relatively homogenous drug compliance among the groups, shorter follow-up period, different population and study design.
This study was based on a multi-institutional standardized EMR database and has several limitations. First, although the CGRD is the largest EMR database in Taiwan and covers almost 10% of the entire population, we could not collect the clinical events that developed in hospitals that were not involved in the CGRD, which may have led to underestimation of the actual event rates. Meanwhile, we used IPTW to balance the confounding medications but any additional drugs from other institutes could not be obtained. However, this should be balanced among the three study groups, and the between-group comparisons should still be reasonable. Second, the BP values used in the present analysis were based on office BP records, which may not represented home BP and ambulatory BP monitoring. Therefore, we could not rule out the possibility of white-coat or masked hypertension. Third, we used PDC as a surrogate marker of medication adherence but we could not ensure that the patients consumed the medications accordingly, and therefore drug compliance may have been overestimated. Finally, this is a retrospective, non-randomized study, and the results may be confounded by other unmeasured factors. Therefore, the results should be interpreted with caution.