Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20

Long-term outcomes of lercanidipine versus other

calcium channel blockers in newly diagnosed
hypertension: a nationwide cohort study

Kai-Hung Cheng, Kai-Chun Cheng, Kai-Yuan Cheng, Yi-Hsin Yang, Chung-Wei

Lee & Wen-Ter Lai

To cite this article: Kai-Hung Cheng, Kai-Chun Cheng, Kai-Yuan Cheng, Yi-Hsin Yang, Chung-
Wei Lee & Wen-Ter Lai (2017) Long-term outcomes of lercanidipine versus other calcium channel
blockers in newly diagnosed hypertension: a nationwide cohort study, Current Medical Research
and Opinion, 33:6, 1111-1117, DOI: 10.1080/03007995.2017.1307817

To link to this article: https://doi.org/10.1080/03007995.2017.1307817

Accepted author version posted online: 16

Mar 2017.
Published online: 13 Apr 2017.

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CURRENT MEDICAL RESEARCH AND OPINION, 2017
VOL. 33, NO. 6, 1111–1117
http://dx.doi.org/10.1080/03007995.2017.1307817
Article ST-0456.R2/1307817
All rights reserved: reproduction in whole or part not permitted

ORIGINAL ARTICLE

Long-term outcomes of lercanidipine versus other calcium channel blockers in

newly diagnosed hypertension: a nationwide cohort study
Kai-Hung Chenga,b , Kai-Chun Chengc,d,j, Kai-Yuan Chenge, Yi-Hsin Yangf, Chung-Wei Leeg,h and Wen-Ter Laii
a
Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; bFaculty of Medicine,
College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; cDepartment of Ophthalmology, Kaohsiung Medical University
Hospital, Kaohsiung, Taiwan; dDepartment of Ophthalmology, Kaohsiung Municipal Hsiao-kang Hospital, Kaohsiung, Taiwan; eDepartment of
Otolaryngology, Head and Neck Surgery, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan; fSchool of Pharmacy,
Kaohsiung Medical University, Kaohsiung, Taiwan; gDivision of Comparative Medicine, Massachusetts Institute of Technology, Cambridge,
MA, USA; hDepartment of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; iDepartment of Internal
Medicine, Kaohsiung Municipal United Hospital, Kaohsiung, Taiwan; jDepartment of Optometry, Shu-Zen Junior College of Medicine and
Management, Kaohsiung, Taiwan

ABSTRACT ARTICLE HISTORY

Objective: Calcium channel blockers (CCBs) have been proved to have beneficial effects on cardiovas- Received 12 September 2016
cular (CV) outcomes, especially in stroke. Lercanidipine, a highly lipophilic CCB, lacks data regarding Revised 28 February 2017
long-term outcomes including: CV, stroke, renal and all-cause mortality. This retrospective cohort study Accepted 14 March 2017
aims to clarify this.
Patients and methods: A total of 144,630 newly diagnosed hypertension (HTN) patients (age: 18–65 KEYWORDS
years) in 2005 from the Taiwan’s National Health Insurance Research Database were enrolled in this Calcium channel blocker;
observational study. A pure hypertension population was fetched by excluding all chronic diseases in cardiovascular mortality;
the Charlson Comorbidities Index. Patients were stratified into the lercanidipine group (n ¼ 1303) and chronic kidney disease;
the propensity-score-matched comparative group (nifedipine, amlodipine or felodipine, n ¼ 15,301). lercanidipine; peripheral
Results: Compared to other CCBs, lercanidipine didn’t have a significant difference on the study end- vascular disease; stroke
points. In individual head-to-head comparisons, lercanidipine was shown to be superior to nifedipine
in incident stroke with an adjusted HR with 95% CI of 0.526 (0.347–0.797) (p ¼ .0025). The key limita-
tions were that personal variables, such as smoking habits, alcohol intake, body mass index and phys-
ical activity and blood pressure profiles were not available in the nationwide registry database.
Conclusion: In newly diagnosed patients with hypertension, lercanidipine was superior to nifedipine in
the six-year period when the analyzed endpoint was stroke.

Introduction spontaneously hypertensive rats, lercanidipine significantly

rescued mild ischemia-induced delayed neuronal death com-
Calcium channel blockers (CCBs) have been reported to be
pared to nicardipine and other antihypertensives11. In the
more effective in preventing heart failure in patients with
DIAL study, lercanidipine showed identical improvement of
coronary artery diseases1,2 and in preventing stroke by reduc-
proteinuria to ramipril in type 2 diabetic patients with hyper-
ing blood pressure variability3–6. Lercanidipine is a third gen-
eration vasoselective dihydropyridine CCB, which causes tension and microalbuminuria12. Additionally, results from
systemic vasodilation by blocking the L-type calcium channel. the ZAFRA study showed that, under lercanidipine, there is
This drug has a high lipophilicity and exhibits a slower onset no significant change in plasmatic creatinine level but there
and longer duration of action than other CCBs7. In addition is an improvement in creatinine clearance in patients with
to its antihypertensive effect, lercanidipine has been reported chronic renal failure during the six-month follow-up13.
to be antiatherogenic and to reduce left ventricular hyper- However, one case regarding acute interstitial nephritis was
trophy8,9. In comparative trials of hypertension management, reported after lercanidipine treatment14. Lercanidipine has
lercanidipine (10–20 mg/day) is as effective as nifedipine slow shown a possible superiority in stroke prevention compared
release (20–40 mg twice daily), nifedipine gastrointestinal to other antihypertensives but little has been reported
therapeutic system (GITS) (30–60 mg once daily), amlodipine regarding the long-term effects on cardiovascular (CV) and
(10 mg/day), and felodipine (10–20 mg/day) in patients with renal outcomes, and mortality compared to other CCBs. This
mild-to-moderate hypertension after 2–16 weeks of therapy7 study aims to clarify the potential long-term effects of lerca-
with lower incidence of adverse effects, particularly lower nidipine-based therapy on the major CV and renal outcomes
leg edema10. In one animal study with stroke-prone and mortality.

CONTACT Wen-Ter Lai [email protected] Department of Internal Medicine, Kaohsiung Municipal United Hospital, No.976, Jhonghua 1st Rd., Gushan
Dist., Kaohsiung City 804, Taiwan
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
www.cmrojournal.com
1112 K.-H. CHENG ET AL.

Patients and methods CCBs: nifedipine, amlodipine and felodipine) based on gen-
der, age, year of diagnosis, occupation and residential area.
Study cohort and patient enrollment
Subjects with significant chronic diseases listed in the
A nationwide observational cohort analysis was performed by Charlson Comorbidities Index were excluded, including myo-
using a two-million cohort database from the Taiwan’s cardial infarction (MI), congestive heart failure (CHF), periph-
National Health Insurance Research Database (NHIRD). The eral vascular disease (PVD), cerebrovascular disease (stroke),
National Health Insurance system is a mandatory universal dementia, chronic pulmonary disease, rheumatic disease,
health insurance program that offers comprehensive medical peptic ulcer disease, liver disease, diabetes mellitus, malig-
care coverage to all residents of Taiwan. NHIRD consists of nancy and AIDS/HIV (Table 1). Furthermore, proteinuria (ICD-
detailed health-care data from >23 million enrollees, repre- 9 code 790.1) and end-stage renal disease (ESRD) were also
senting >99% of Taiwan’s population. The patients’ identifi- excluded (Figure 1).
cations were encrypted, and a linkage between the
diagnostic claims and each patient was assigned within this
Study endpoints and patient follow-up
database to enable continuous follow-up. The two million
cohort database in 2005 is a random sample from the NHI In this six-year study, we linked the National Death
beneficiaries in 2005. The database is managed by the Certificate Registry data with the identified death marker and
Collaboration Center of Health Information Application expired date from 2005 to 2011 to calculate the mortality
(CCHIA), Ministry of Health and Welfare. For protection of rate in each group. We also linked the inpatient data with
confidentiality, patient identification had been already identified endpoints after index date including MI, CHF,
encrypted, and the authorized researchers were only permit- stroke, dementia, chronic kidney disease, nephrotic syn-
ted to perform data linkage, and processing statistical ana- drome, ESRD, peripheral artery disease (PAD, ICD-9-CM codes
lysis with a specified computer in a closely monitored room. 440.2, 440.3, 440.8, 440.9, 443, 444.22, 444.8, 447.8, and
Using the scrambled personal identifier for each subject, the 447.9)16 and newly onset DM. In order to get precise diagno-
researchers are able to link the files to obtain socio-demo- sis, hospitalization and principal diagnosis of those endpoints
graphic information, longitudinal medical history and other including MI, CHF, stroke and dementia and nephrotic syn-
information. Only statistical results were allowed to be drome were required. The claims-based diagnosis of CKD was
brought out. defined by the presence of three consecutive entries of ICD-
Newly diagnosed hypertensive (HTN, ICD-9 codes 9-CM code 58517 in the claims without catastrophic illness
401.0–401.9) patients between 18 and 65 years old receiving registration cards for ESRD (indicating the need for renal
continuous CCB-based therapy with one of four CCBs (lerca- replacement therapy). A nationwide CKD preventive project
nidipine, nifedipine, amlodipine and felodipine) for more covering CKD stages 1–5 was launched by the Taiwan
than nine months and without other significant chronic dis- Society of Nephrology in 2004. The simplified Modification of
eases were enrolled. In addition, uninterrupted CCB therapy Diet in Renal Disease equation along with proteinuria has
in this cohort during the study period was required. been used to estimate the national prevalence of 5-stage
Adherence is the number of CCBs prescribed over the study CKD in Taiwan18,19. The ICD-9-CM code 585 is consistent with
period without dose or number reduction every month from the National Kidney Foundation’s Kidney Disease Outcome
the start until the end of study. Since only those adherent Quality Initiative definition of CKD stages 1–519, allowing for
and/or persistent to the CCBs were enrolled, they had pre- comparisons of the incidence and prevalence of CKD in
sumably had little in the way of side effects15. Therefore, per- Taiwan and the United States20. However, the CKD stage
fect adherence and persistence were needed for this cohort. (severity) cannot be assessed in the NHIRD. ESRD was identi-
The lercanidipine group was matched with similar propensity fied by the requirement of renal replacement therapy which
scores (1:4 ratio) to the comparative group (old generation was confirmed by (1) specific International Classification of

Table 1. ICD-9-CM coding algorithms for Charlson comorbidities.

Diagnostic Categories Deyo’s ICD-9-CM codes
Myocardial Infarction 410.x, 412.x
Congestive Heart Failure 428.x
Peripheral Artery Disease 440.2, 440.3, 440.8, 440.9, 443, 444.22, 444.8, 447.8, and 447.9
Cerebrovascular Disease 430.x–438.x, 342.x, 344.1
Chronic Pulmonary Disease 490–496, 500–505, 506.4
Rheumatic Disease 710.0, 710.1, 710.4, 714.0–714.2, 714.81, 725.x
Peptic Ulcer Disease 531.4x–531.7x, 532.4x–532.7x, 533.4x–533.7x, 534.4x–534.7x, 531.0x–531.3x,
532.0x–532.3x, 533.0x–533.3x, 534.0x–534.3x, 531.9, 532.9, 533.9, 534.9
Mild Liver Disease 571.2, 571.4–571.6
Diabetes without Chronic Complications 250.0x–250.3x, 250.7x
Diabetes with Chronic Complications 250.4x–250.6x
Chronic Kidney Disease 585
Any Malignancy, Including Lymphoma and Leukemia, Except Malignant 140.x–172.x, 174.x–195.8, 200.x–208.x
Neoplasm of Skin
Moderate or Severe Liver Disease 456.0–456.21, 572.2–582.8
Metastatic Solid Tumor 196.x–199.1
AIDS/HIV 042.x–044.x
 LERCANIDIPINE AND LONG-TERM CARDIOVASCULAR OUTCOMES 1113

Figure 1. Study flow. HTN: hypertension; CCI: Charlson Comorbidities Index (Table 1); CCB: calcium channel blocker. Not meet: no corresponding (close) propensity
score met.

Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) in the lercanidipine and comparative groups groups20.
codes of 585.x (chronic kidney disease) plus (2) confirmed Patients without a corresponding match were excluded. The
procedure codes (58001C, 58027C, 58029C for hemodialysis; mortality, incidences of MI, CHF, stroke, renal disease, neph-
58002C, 58011AB for peritoneal dialysis and 58011A for con- rotic syndrome, ESRD, PAD and newly onset DM were
tinuous ambulatory peritoneal dialysis) and (3) inclusion in assessed using Kaplan–Meier curves and Cox proportional
the Registry for Catastrophic Illness Patient Database, a sub- hazards models in this prospective observational cohort
classification of the NHIRD. In addition, in order to get pre- study21. Multivariate-adjusted hazard ratios (HR) were com-
cise primary PAD, patients with histories of coagulopathies puted from Cox regression with the further adjustment of
(ICD-9-CM codes 286, 289.8), sickle-cell disease (ICD-9-CM gender, age, education, income status, residential area and
codes 282.6), age <18 years, or missing information, were marital status. Statistical analysis was performed using SAS
excluded16. Each patient was followed from index date to 9.1 software (SAS Institute Inc., Cary, NC, USA). All statistical
expired date or censored data of the endpoints and other significances were set at a p < .05.
identified procedures during the study period.
Results
Statistical analysis Patients
Thus, we used propensity matching to reduce potential con- From 1 January 2005 to 31 December 2005, a total of
founding and selection bias and to balance the characteris- 144,630 newly diagnosed HTN (ICD-9 codes 401.0–401.9)
tics of patients included in the lercanidipine and comparative patients aged between 18 and 65 years old were identified
groups. Propensity scores were calculated using multivariable from the NHIRD as the study population. After excluding the
logistic regression with all variables in Table 2 to estimate chronic diseases listed in the Charlson Comorbidities Index
probability for administration of the two groups. The and fetching subjects treated with CCB-based therapies con-
GMATCH macro provided by Mayo Clinic was used to per- tinuously for more than nine months, 1303 subjects on lerca-
form a 1:4 matching with nearest-neighbor matching of nidipine-based therapies (lercanidipine group) and 15,301
caliper in 0.02 standard deviation for matching patients subjects on old-generation CCB-based therapies (comparative
1114 K.-H. CHENG ET AL.

group) were identified through 1:4 matching with similar pro- Mortality and endpoints during the six-year follow-up
pensity scores. No subjects were lost to follow-up. In add-
The mean follow-up periods were 6.11 ± 0.01 and 5.45 ± 0.02
ition, uninterrupted CCB therapy was required in this cohort
years in the lercanidipine and the comparative groups,
during this six-year study period and there was no loss of fol-
low-up in this study. respectively. During the follow-up period, there was no differ-
ence in the overall primary composite endpoint between the
two groups with 235 in the lercanidipine group and 907 in
Baseline characteristics the comparative group and the hazard ratio (HR) with 95%
confidence interval (CI) after adjusting for education, income,
There was no difference in age, sex or marital status between
area and marital status was 0.998 (0.793–1.074) (p ¼ .2988)
the lercanidipine and comparative groups. The highest edu-
(Table 3). As to mortality, there was no difference with 118
cation and income levels were significantly higher in patients
patients expired in total, 16 in the lercanidipine and 102 in
in the lercanidipine group. Geographically, there were more
the comparative CCB groups, with the HR with 95% CI of
subjects in the lercanidipine group living in Taipei, the capital
0.632 (0.306–1.305) (p ¼ .2145) after adjustment (Table 3).
of Taiwan, while there were more subjects in the compara-
There was a non-significant increase in the incidence of CKD
tive group living in Southern Taiwan and the Kaohsiung-
in the lercanidipine group (n ¼ 29, 2.3%) compared to the
Pingtung area (Table 2).
comparative group (n ¼ 88, 1.7%) and the adjusted HR with
95% CI was 1.644 (0.966–2.799) (p ¼ .0669) (Table 3).
Table 2. Baseline characteristics. Nonetheless, there was no ESRD discovered in either group
Characteristic (1:4 match) Lercanidipine Comparative p-value during the follow-up period. There were no significant differ-
N % N % ences in hospitalized MI, hospitalized CHF, hospitalized
Age – years (mean ± SD) 1284 48.61 ± 9.68 5136 48.61 ± 10.10 1.0000
stroke, hospitalized nephrotic syndrome, peripheral artery
Median 50 50 disease, peptic ulcer disease or new onset of DM between
Interquartile range 18–65 18–65 the two groups (Table 3). Furthermore, the individual head-
sex – n (%) to-head comparisons of lercanidipine with nifedipine and ler-
Male 802 62.46 3208 62.46 1.0000
Female 482 37.54 1928 37.54 canidipine with felodipine were investigated. The number of
Highest education level subjects on pure amlodipine use was too small (n ¼ 19) to do
Elementary school graduates 335 26.09 1402 27.30 .2838 an adequate comparison with lercanidipine. This is because
Junior high graduates 268 20.87 1125 21.90 amlodipine widely serves as the key element for combination
Senior high graduates 382 29.75 1536 29.91
Bachelor’s degree and above 299 23.29 1073 20.89 therapy for hypertension currently. Figure 2 shows lercanidi-
Income level pine to be superior to nifedipine in stroke with adjusted HR
<NT$28,000/year 547 42.60 2149 41.84 .6249 with 95% CI of 0.526 (0.347–0.797) (p ¼ .0025). In addition,
NT$28,000/year 737 57.40 2987 58.16 there was a non-significant decrease of CCB related peptic
Area ulcer in lercanidipine compared to nifedipine with adjusted
Taipei 615 47.90 2454 47.78 .2357
Northern Taiwan 170 13.24 739 14.39 HR with 95% CI of 0.602 (0.346–1.046) (p ¼ .0719). In addition,
Central Taiwan 218 16.98 832 16.20 there was a non-significant increase of CKD in lercanidipine
Southern Taiwan 128 9.97 527 10.26 compared to felodipine with adjusted HR with 95% CI of
Kaohsiung-Pingtung 130 10.12 532 10.36
Eastern Taiwan 23 1.79 52 1.01 2.157 (0.98–4.751) (p ¼ .0563).
Marital status
Single 193 15.03 772 15.03 .4252 Discussion
Married 958 74.61 3893 75.80
Divorced/widowed 133 10.36 471 9.17
To the best of our knowledge, this is the first and biggest
Comparative group including nifedipine/amlodipine/felodipine; p < .05.
observational study to explore the mortality, cardiovascular

Table 3. Outcomes.
Endpoint Lercanidipine (N ¼ 1284) Nifedipine/Amlodipine/Felodipine (N ¼ 5136) Hazard Ratio p-value
No. of Patients No. of Patients (95% CI)
Death (all cause) 16 102 0.632 (0.306, 1.305) .2145
Death (CV): Myocardial Infarction þ Congestive 0.852 (0.132, 5.497) .8663
Heart Failure þ Stroke
Myocardial Infarction (hospitalized) 6 22 0.623 (0.159, 2.435) .4959
Congestive Heart Failure (hospitalized) 9 33 1.448 (0.470, 4.460) .5193
Stroke (hospitalized) 35 177 0.761 (0.504, 1.149) .1938
Peripheral Artery Disease (>3 consecutive visits) 19 67 1.068 (0.534, 2.138) .8516
Chronic Kidney Disease (>3 consecutive visits) 29 88 1.644 (0.966, 2.799) .0669
Peptic Ulcer Disease (hospitalized) 20 110 0.704 (0.393, 1.260) .2370
Diabetes Mellitus (>3 consecutive visits) 149 519 1.146 (0.923, 1.423) .2171
Nephrotic Syndrome (hospitalized) 0 0 — —
End-stage Renal Disease (hospitalized) 0 0 — —
Data computed by Kaplan–Meier and Cox regression.
—, events were too scanty to calculate the HRs between the two groups.
Adjusting for education, income, area, marital status.
p < .05.
 LERCANIDIPINE AND LONG-TERM CARDIOVASCULAR OUTCOMES 1115

Figure 2. Endpoints compared between lercanidipine and nifedipine. Lercanidipine is superior to nifedipine in stroke with adjusted HR with 95% CI of 0.526
(0.347–0.797) (p ¼ .0025). In addition, there was a non-significant decrease of CCB related peptic ulcer in lercanidipine compared to nifedipine with adjusted HR
with 95% CI of 0.602 (0.346–1.046) (p ¼ .0719).

Figure 3 Endpoints between Lercanidipine and Felodipine. Lercanidipine is inferior than felodipine in primary endpoint and the adjusted HR with 95% CI were
1.284 (1.029–1.603) (p ¼ .0271). In addition, there was a non-significant increase of CKD in lercanidipine compared to felodipine and the adjusted HR with 95% CI
were 2.157 (0.98–4.751) (p ¼ .0563).

and renal endpoints, and other soft endpoints for lercanidi- Endpoints compared between lercanidipine and other
pine, a highly lipophilic third generation CCB, in a compara- calcium channel blockers
tive model in a population with newly diagnosed pure
hypertension without significant chronic disease. There was There was no significant difference in any endpoint between
no significant difference in all-cause mortality or other indi- the lercanidipine and comparative groups after adjusting
vidual endpoints between the lercanidipine group and the for education, income, area and marital status in our study.
comparative (nifedipine, amlodipine and felodipine) group It is well known that hypertension increases morbidity and
after adjusting for education, income, area and marital status. mortality22, which were decreased by antihypertensive treat-
For head-to-head comparisons, lercanidipine was superior to ment23. For efficacy, lercanidipine 10–20 mg/day is as effect-
nifedipine in stroke prevention and there was a non-signifi- ive as nifedipine slow release (SR) 20–40 mg twice daily,
cant decrease of CCB related peptic ulcer in lercanidipine amlodipine 10 mg/day, felodipine 10–20 mg/day, and nifedi-
compared to nifedipine. However, there was a non-significant pine GITS 30–60 mg once daily7. Therefore, it is plausible that
increase of CKD in the lercanidipine group. lercanidipine is similar to other CCBs in mortality reduction
1116 K.-H. CHENG ET AL.

due to the similar BP lowering effect. However, there was a risk of ESRD35. The incidence of ESRD in this study is presum-
non-significant increase of CKD with lercanidipine use. A ably higher than in the general population. However, no inci-
plausible explanation is that lercanidipine acts more slowly dent ESRD was reported during the six years of follow-up.
than older dihydropyridines24 and from the VALUE (Valsartan This result might indicate that lercanidipine did not increase
Antihypertensive Long-term Use Evaluation) study, it is the hard endpoint of ESRD despite the increase in renal dis-
known that the rapid reduction of blood pressure produces a ease. However, a further prospective long-term study is still
great impact on CV risk reduction25. needed to clarify this observation.

Endpoints compared between lercanidipine and Limitations

nifedipine The present study had some limitations. First, personal varia-
Our data showed that there was a significant reduction in bles, such as smoking habits, alcohol intake, body mass index
the incidence of stroke in the lercanidipine group compared and physical activity, were not available in the nationwide
to the nifedipine group. Recent studies have shown that registry database. Second, the comorbidity results relied on
CCBs could reduce the BP variability and have a better effect the claims data on the ICD-9-CM diagnosis codes, which
on stroke prevention than other classes of antihypertensive could have potentially led to disease misclassification.
drugs6,26. Lercanidipine is a third generation vasoselective Therefore, we took hospitalized follow-up records of cardio-
dihydropyridine CCB with highly lipophilic activity that exhib- vascular events with the main ICD-9-CM diagnosis codes as
its a longer duration of action than other CCBs by its parti- incident events to minimize the misclassification. In addition,
tioning into the lipid bilayer of cell membranes where it we linked the National Death Certificate Registry data to
forms a depot, followed by diffusion to the receptor binding identify the mortality. Third, BP profiles were not available
site7,27. Therefore, compared to other CCBs, the depot effect from NHIRD and the details of BP control were unknown.
of lercanidipine contributes a longer antihypertensive action Owing to the limitations mentioned above, a large-scale, pro-
lasting for at least 24 hours and no significant increase in spective trial is necessary to confirm the findings presented
heart rate. Consequently, the superiority for stroke preven- here. Fourth, there are some issues to consider in evaluating
tion of lercanidipine may be related to the lowering effect an observational cohort study. One issue is the loss of follow-
on both BP and HR variabilities. The peripheral arterial stiff- up, but this NHIRD represents >99% of Taiwan’s population
ness may be reduced by CCBs due to the increase in nitric and no one was lost during follow-up in our study. Second,
oxide (NO) bioavailability and decrease in oxidative stress, it is often difficult to blind the investigators who are assess-
thereby improving endothelial activity and vascular func- ing the study’s outcomes. However, both the exposure status
tion28. In contrast, nifedipine rapidly lowers blood pressure and outcomes of the study participants were assessed by
which may induce dizziness or fainting and reflex tachycardia their own doctors who neither participated nor knew this
after taking the first few doses. The complications are much study which may have attenuated the influence of bias on
less frequent in the sustained-release preparations of nifedi- the assessment of the outcome. The advantage of the obser-
pine. The short action of nifedipine could cause large fluctua- vational cohort study design is the possibility of assessing
tions in blood pressure and could be harmful when taking the incidence rates, relative risks, and causality21.
higher doses9. Lercanidipine also had a non-significant lower
incidence of CCB-related peptic ulcer than nifedipine. The Conclusion
esophageal acid exposure time has been reported to be sig-
nificantly longer with the administration of nifedipine29 and In patients with newly diagnosed hypertension and without
nifedipine might have a corrosive effect30. significant chronic diseases, lercanidipine produced no signifi-
cant differences in any of the primary and secondary end-
points compared to other old CCBs. When considering
Endpoints compared between lercanidipine and
individual head-to-head comparisons, lercanidipine produced
felodipine
a significant reduction in the incidence of stroke compared
There was a non-significant increase in CKD in the lercanidi- to nifedipine after the six-year follow-up.
pine group. It has been reported that felodipine initially
causes a significant increase in renal blood flow, even with a
Transparency
non-significant change in systemic blood pressure, and does
not alter the perfusion and tubular function of the kidneys in Declaration of funding
long-term therapy31. In addition, felodipine pretreatment pro-
This manuscript received no funding.
vided significant protection to renal function in the setting of Author contributions: K.-H.C. participated in the generation of the ori-
acute ischemic renal injury32,33. The ZAFRA study was a ginal ideas, in the study design and in the analysis of data, in drafting of
short-term study showing the improvement in creatinine the manuscript, in revising it critically for important intellectual content
clearance with lercanidipine in a CKD population13, but the and in final approval of the manuscript submitted. Other authors partici-
pate in 1) conception and design or analysis and interpretation of data,
long-term result remained unknown in this study. In terms of
or both: K.-C.C., K.-Y.C., Y.-H.Y. and W.-T.L.; 2) drafting of the manuscript
the true hard renal outcome of ESRD, it is known that the or revising it critically for important intellectual content: Y.-H.Y., C.-W.L.
general incidence is 331 per million population in 2001 in and W.-T.L.; and 3) final approval of the manuscript submitted: Y.-H.Y.
Taiwan34 and hypertension per se is known to double the and W.-T.L.
 LERCANIDIPINE AND LONG-TERM CARDIOVASCULAR OUTCOMES 1117

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acute interstitial nephritis, never reported before. Nephrology
K.-H.C., K.-C.C., K.-Y.C., Y.-H.Y., C.-W.L., and W.-T.L. have disclosed that 2013;18(Suppl S1):71 abstr. 224
they have no relationships with or financial interests in any commercial 15. Chan DC, Chang CH, Lim LC, et al. Association between teripara-
companies related to this study or article. tide treatment persistence and adherence, and fracture incidence
CMRO peer reviewers on this manuscript have no relevant financial in Taiwan: analysis using the National Health Insurance Research
or other relationships to disclose. Database. Osteoporos Int 2016;27:2855-65
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