Hepatocellular Carcinoma: Overcoming Challenges in Disease Management
(read article below)
Safety Profile: The Benefits of Lipophilicity (read article
the Clinical Paradigm: Treating Systolic Blood Pressure to Goal (read
Multicenter, Randomized, Double-Blind, Parallel Group Study Comparing
the Efficacy of a Fixed-Dose Combination of Amlodipine plus Benazepril
HCl Versus Amlodipine in the Treatment of Stage 2 and Stage 3 Hypertension
(The Solace Study Write Up.) (read article below)
(Avoiding Cardiovascular Events Through Combination Therapy in Patients
Living with Systolic Hypertension): Trial Design and Rationale
by Kenneth A. Jamerson; George L. Bakris; Bjørn Dahløf;
Bertram Pit; Eric Velzaquz; Michael A Weber (read article below)
Overcoming Challenges in Disease Management
G. Gish, MD
of Hepatology and Complex GI,
Physician’s Foundation at CPMC and
Departments of Medicine and Transplantation,
California Pacific Medical Center, San Francisco, California
used in this paper: AFP, alpha-fetoprotein; AFP-L3%, lectin-reactive
AFP percent; CT, computed tomography; HBV; hepatitis B virus; HCC, hepatocellular
carcinoma; HCV, hepatitis C virus; MELD, model for end-stage liver disease;
MRI, magnetic resonance imaging; NAFLD, nonalcoholic fatty liver disease;
RR, relative risk.
requests for reprints to: Robert G. Gish, MD, Division of Hepatology
and Complex GI, Physician’s Foundation at CPMC and Departments
of Medicine and Transplantation, California Pacific Medical Center,
2340 Clay St, San Francisco, CA 94115. E-mail: firstname.lastname@example.org;
Fax: (415) 776-0292.
Hepatocellular carcinoma is the third most frequent cause of death from
cancer and the eighth most commonly occurring cancer in the world. In
the United States, hepatocellular carcinoma appears to be increasing
along with chronic hepatitis infection, especially in immigrants, a
major risk group population. A disease of multifactorial etiology, hepatocellular
carcinoma confers many management challenges. Hepatocarcinogenesis is
a multistep process involving different genetic alterations that ultimately
lead to malignant transformation of the hepatocyte. Early hepatocellular
carcinoma is characteristically silent and slow growing with few symptoms
occurring until late in disease evolution. Early and accurate diagnosis
of hepatic tumors relies on clinical suspicion, screening protocols,
serologic testing, radiologic imaging, and tissue confirmation. Lack
of clinically validated biomarkers as well as clinical identification
of hepatocellular carcinoma at either early or advanced disease makes
diagnosis and treatment difficult. Advances in computed tomography and
magnetic resonance imaging have markedly increased the sensitivity and
specificity of testing yet are still flawed with a relatively high false-positive
rate. Several surgical and non-surgical therapies have been developed
and employed with varying degrees of success. Options include surgical
resection, liver transplantation (the only curative treatment), local
ablation therapies, and pharmaceutical interventions. At 5 years after
resection, the recurrence rate ranges between 30% and 60%. In patients
with nonresectable disease, prognosis is dismal, with a median survival
of less than 12 months even with chemotherapy. The medical community
faces numerous challenges in hepatocellular carcinoma and must work
toward better management and multidisciplinary care of this complex
Hepatocellular carcinoma (HCC) is a leading solid organ malignancy worldwide
due to its common etiology from chronic liver damage due to hepatitis
or cirrhosis. A malignancy of worldwide significance, HCC has become
increasingly important in the United States likely due to its complex
factors involving a growing incidence of hepatitis C virus (HCV). A
disease of multifactorial etiology, HCC confers many management challenges
including variable morphology, poor prognosis, lack of validated serologic
markers and imaging techniques, lack of national guidelines for screening
or treatment, and a need for coordinated medical care and better overall
screening strategies. Multiple specialties are required for optimal
early detection, diagnosis, and treatment, demanding a multidisciplinary
and multimodality approach. A thorough exploration of the ever-changing
status of HCC is warranted. This article offers a comprehensive overview
of the epidemiology, characteristics, diagnosis, and treatment of HCC
with a discussion of particular challenges and the role of the hepatologist
in the management of disease.
With an incidence of half a million to a million cases per year, nearly
equal to its mortality rate, HCC is the world’s fifth most common
solid tumor1 and third most frequent cause of cancer death.2 As summarized
in Table 1, disease prevalence varies widely. HCC cases are heavily
concentrated in Asia and sub-Saharan Africa, where more than 30 new
cases per 100,000 persons are diagnosed each year.3 Generally speaking,
older age and male gender carry a greater risk for development of HCC.4
Men develop HCC more often than women in all populations, with male-to-female
ratios reported from 2:1 to 8:1.5 This may be due to androgen receptors
on HCC6 or an increased prevalence of viral hepatitis and/or alcoholic
cirrhosis in men.7
has been given to a recent increased risk of HCC in western regions.
Over the past decade, the United States has documented a startling increase
in HCC cases.8 Although HCC represents <2% of all United States tumors,
its incidence of 1 to 4 cases per 100,000 population continues to increase
at an alarming rate.9 The cause for this increase is not entirely understood,
though it is clearly linked to a rise in chronic hepatitis C.10
theories have been proposed to explain the fact that 18,000 new cases
of HCC are projected to occur in the United States in 2005.1 One such
theory attributes the recent rise in HCC risk to the complex epidemics
of increased risk in HCV patients as the disease evolves to cirrhosis
and hepatitis B virus (HBV) in immigrant populations.11 A recent population-based
study found that the risk for HCV-related HCC and HBV-related HCC has
increased by 226% and 67%, respectively, while idiopathic HCC has decreased
from 43% to 39%.9 A second theory implicates alcohol abuse, which afflicts
more than 18 million American adults, comprising a prevalence that is
5 times higher than that of hepatitis C.12 The concomitant occurrence
of alcohol use and chronic hepatitis C doubles the risk of HCC compared
with that of hepatitis C alone. Moreover, a synergistic effect has been
proposed for concomitant alcohol intake and hepatitis C infection in
the development of HCC.12
have attempted to link HCC to nonalcoholic fatty liver disease (NAFLD)-associated
cirrhosis and to diabetes, which are increasing in the United States1,13,14
HCC is multifactorial in etiology and varies by region. Nonetheless,
several major and minor causal associations with the tumor have been
identified, as demonstrated in Table 2.
tenth most common cause of death in the United States, liver cirrhosis
is present in up to 80% of patients with HCC, is precursory to the development
of HCC,1 and greatly affects patient prognosis and tolerance of treatment.
In the United States, HCV infection, alcohol use, and NAFLD are the
most common causes of cirrhosis.1 This trend is expected to continue
due to the estimated 4 million hepatitis C-seropositive Americans and
the known latency of HCC development from the initial HCV infection,
which may take 2 to 3 decades to develop.1,15 Moreover, HCV with cirrhosis
and HBV with or without cirrhosis are also major coexistent etiological
agents that lead to the development of HCC.16 Though there is no direct
evidence that HCV is oncogenic, it may nonetheless promote carcinogenesis
through the induction of chronic necroinflammatory hepatic activity
and liver cirrhosis.17
and Disease Characteristics
As with most types of cancer, hepatocarcinogenesis is a multistep process
involving different genetic alterations that ultimately lead to malignant
transformation of the hepatocyte.18 The molecular contribution of the
multiple factors and their interactions in hepatocarcinogenesis are
still poorly understood, suggesting however that HCC is genetically
a very heterogeneous tumor. As shown in Figure 1, malignant transformation
of hepatocytes may occur regardless of the etiological agent through
a pathway of increased liver cell turnover, induced by chronic liver
injury and regeneration in a context of inflammation and oxidative DNA
characteristically silent and slow growing, with most patients having
few symptoms until very late in the disease;19 often these symptoms
are related to decompensated liver disease rather than directly due
to the tumor. As with other malignancies, the natural history of HCC
relates to patterns of growth, the severity of the underlying cirrhosis,
and the effect of the tumor on liver function in those patients with
marginal reserve as well as the propensity to invade vasculature and
spread to surrounding and distant organs. Features of HCC have been
shown to indicate more aggressive behavior, including (a) poorly differentiated
histology, (b) lack of fibrous capsule, (c) large size (>5 cm in
diameter), and (d) elevated serum levels of alpha-fetoprotein (AFP).3
The most common form of HCC is an adenocarcinoma, which may be unifocal,
diffuse or multifocal at presentation.
rates have a wide range of variability even among patients from the
same region and regardless of disease stage.3 The development of liver
cell dysplasia is a well-recognized premalignant finding in patients
with cirrhosis of any etiology.20 Maturation of HCC requires adequate
vasculature, which is derived primarily by the hepatic arterial network.
Characteristic satellite lesions may subsequently develop and eventually
progress to form multinodular disease and invasion of large vascular
Presentation and Prognosis
Clinical presentation of disease varies depending on hepatic reserve,
and may include malaise, anorexia, abdominal pain, abdominal fullness
due to ascites or mass effect, or weight loss.3 However, 40% of HCC
patients are asymptomatic, making early diagnosis and detection of the
disease difficult. A more complete schema of symptoms is presented in
expectancy of patients with newly diagnosed HCC has classically been
measured in weeks to months with a mortality/incidence ratio close to
1.21 In patients with nonresectable disease, prognosis is dismal, with
a median survival less than 12 months even with chemotherapy.22,23 Furthermore,
prognosis is strongly linked to degree of hepatic impairment,3 with
the outlook for cirrhotic patients least promising without liver transplant.
In view of the poor prognosis of patients with HCC, attempts have been
made to manage disease by preventive measure (vaccination), treatment
of viral infections if present, and prevention of cirrhosis.
Accurate diagnosis of hepatic tumors relies on clinical suspicion, serologic
testing for tumor markers, radiologic imaging, and tissue confirmation.
The most common serologic marker used in HCC diagnosis is AFP, an alpha1-globulin
produced in fetal, regenerating, and malignant hepatocytes. AFP is elevated
in 60% to 80% of patients with HCC, and the level is dependent, in part,
on the size of the tumor.36 Values have a wide variability for the diagnosis
of HCC and there is a high rate of false positives with the assay.
lectin-reactive AFP percent (AFP-L3%) was added to the diagnostic armamentarium
as an advanced option for detecting HCC, trending patients, and prognosis.
It has been noted that patients with AFP-L3_negative liver cancer after
treatment have a longer cumulative survival rate, and less recurrence
rate.25 An AFP-L3 level of over 10% has a specificity of 91% vs 61%
for an AFP level of 10 ng/mL indicating a low false-positive rate with
AFP-L3% detection. Also the relative risk (RR) of developing HCC was
9.2 for an AFP-L3 over 10% whereas the RR for AFP over 10 and 100 ng/mL
was approximately 7.26 When patients demonstrate a shifting value from
low AFP-L3% to a high AFP-L3% value, triple-phase computed tomography
(CT) should be performed to detect HCC.
Liver ultrasound, CT scan, and magnetic resonance imaging (MRI) are
the common imaging techniques employed variously to identify HCC. The
complexity of diagnosis may play an important role in the late diagnosis
of tumors; however, Figure 2 offers a suggested algorithm for enhanced
diagnostic follow-up after abnormal surveillance or clinical suspicion.27
Due to the noninvasive nature, good sensitivity for larger lesions,
and lower cost of ultrasound, it is the preferred mode of screening.28
A triphasic hepatic acquisition helical CT scanning technique has become
an additional standard method for clinical diagnosis, though hepatic
angiography is also widely used.29 Lipiodol CT is one of the most sensitive
preoperative evaluation methods in detecting metastatic nodules ≤1
cm,30 whereas MRI is often thought to be better for defining tumor morphology
than CT scanning.27
Diagnosis of HCC relies on cytohistologic evidence. The sample for pathologic
examination is usually obtained by means of percutaneous fine-needle
aspiration or biopsy. However, false-negative results may occur in 40%
of cases with small tumors.31 Therefore, biopsy is a useful tool, but
not a required procedure in the confirmation of HCC and may result in
spread of HCC.
Historically, the most commonly used clinical staging system is that
developed by Okuda et al.32 The patient is evaluated based on clinical
criteria such as presence of ascites, serum albumin levels, bilirubin
concentration, and tumor size. This system has prognostic implications,
as it takes into consideration the severity of underlying liver cirrhosis;
however it does not identify patients at early stages of disease. The
tumor-node-metastasis staging classification uses size, presence of
vascular invasion, lymph node status, and metastatic disease as prognosticators
of outcome (Table 4);33 though promising, this system does not take
into account underlying disease of the liver and co-morbidity such as
With much debate in the literature, several other prognostic systems
have been developed (Table 4).33 These systems are intended to be more
comprehensive for advanced diagnosis and management, as well as better
stratification of patients entering clinical trials, and are currently
Several surgical and non-surgical therapies have been used in the treatment
of HCC with varying degrees of success. Options include surgical resection,
liver transplantation (the only curative treatment), local ablation
therapies, and pharmaceutical interventions. The choice of therapy is
determined by the extent of tumor burden and degree of underlying liver
disease.34 Careful decision making concerning tumor staging, cirrhosis,
and general patient health is advisable.35 A multidisciplinary approach
has been suggested for optimal treatment success.36
a complex neoplasm for which there are no treatment guidelines and no
consensus regarding prognosis and therapeutic approach. The therapeutic
strategies currently published in the literature differ in terms of
their selection of candidates and indications for treatment. A comprehensive
approach to HCC treatment based on the Barcelona Clinic Liver Cancer
staging system is presented in Figure 3.37
in-depth look at the appropriateness of surgical approaches in patients
without cirrhosis (Figure 4) and with cirrhosis (Figures 5 and 6) is
further illustrated for clarification in the management algorithms.38
difficulties arise when dealing with patients with cirrhosis as tolerance
of treatment may be substantially reduced due to liver dysfunctions
and intolerance to agents, which include doxorubicin, portal hypertension,
associated decreased platelet counts and serum albumin level with a
reduced intravascular compartment and hence reduced glomerular renal
perfusion and inability to administer agents such as cisplatin. Therefore,
there is a need to identify agents that can be tolerated by patients
with liver cirrhosis.
Surgical Intervention: Liver Resection
Liver resection is fundamental in the multidisciplinary approach to
HCC and should always be considered as a first choice in the absence
of extrahepatic disease.34 However in the western world, only 5% of
cases occur in noncirrhotic individuals.38 At 5 years after resection,
the recurrence rate ranges between 31% and 56%.34,39,40 Pathological
predictors of recurrence are microvascular invasion, satellite nodules,
and poor differentiation of the tumor.41 The liver is the first site
of recurrence in up to 90% of patients,42 with secondary metastases
at the lung, adrenal glands, and bones.43 Isolated extrahepatic recurrences
are uncommon. Prevention of tumor relapse has been attempted with internal
radiation with iodine-131,44 retinoids, 45 and immunotherapy.46
Liver transplantation is the most effective intervention and only curative
treatment for HCC patients with cirrhosis and no extrahepatic disease.
Transplantation removes the tumor itself and cures preneoplastic disease.
However, many patients are not suitable candidates due to advanced disease,
while others often experience tumor progression and death during the
wait for a cadaveric donor.47 Optimal transplant patients are those
with single HCC <5 cm or with 3 or fewer nodules <3 cm, without
extrahepatic or vascular spread.1 These selection criteria lead to survival
rates >70% at 5 years and recurrence rates <15%.41 There have
been recent challenges to this selection criteria, with some centers
suggesting expanded criteria.
for end-stage liver disease (MELD) scoring system was developed to prioritize
patients for donation according to bilirubin level, prothrombin activity,
and creatinine level in order to give priority to HCC patients and minimize
dropout rates.48 MELD has been shown to predict accurately the 3-month
mortality for cirrhotic patients awaiting transplantation.49 Recent
changes in MELD assigned a lower score to patients with HCC tumors with
size between 2 and 5 cm and eliminated additional points for patients
with tumor size under 2 cm due to excellent short-term survival. Also,
data has emerged demonstrating that up to 30% of patients with tumors
by advanced imaging did not have HCC, highlighting the high-false positive
rate of triphasic CT and MRI imaging if tumors were less than 2 cm in
size. Most of these lesions were likely regenerative nodules or dysplastic
lesions, both of which have an excellent short- and intermediate-term
Local Tumor Ablation
Percutaneous ablation is considered the best option for early, nonsurgical
HCC. Several methods have been developed, including intratumoral injection
of ethanol or acetic acid, as well as thermal ablation with liquid nitrogen
(cryoablation), microwaves, laser, and radiofrequency.34 Percutaneous
ethanol injection is one of the most widely used of these modalities,
and is considered the standard for treating small HCC51 and is recommended
for small nonresectable lesions or patients at risk for surgery due
to comorbidity.52 Initial complete response rates inversely correlate
with tumor size and account for 95% and 70% of cases in tumors of 2-cm
and 3-cm diameters, respectively.53
For patients with failed curative treatments, or who are not candidates
for radical therapies, several non-surgical options may be considered.
Palliative therapies for intermediate to advanced HCC include embolization/chemoembolization,
tamoxifen and other hormonal compounds, arterial or systemic chemotherapy,
internal radiation with iodine-131, immunotherapy, and interferon.43,54,55
embolization is the most widely used primary treatment for nonresectable
HCC and is the most used therapy for patients awaiting liver donation
for the prevention of HCC progression that might preclude transplantation.54
Obstruction of the hepatic artery with an embolization agent induces
extensive necrosis in large vascularized HCC. Embolization agents, usually
gelatin, may be administered together with selective intra-arterial
chemotherapy (doxorubicin, mitomycin, or cisplatin) mixed with Lipiodol
(chemoembolization). This approach achieves a partial response in 15%
to 55% of patients, often significantly delaying tumor progression and
vascular invasion.54 Internal radiation with 131-I labeled Lipiodol
or arteriolized lipiodolization (chemotherapeutic agents and Lipiodol)
provides response rates above 20%.54 Systemic doxorubicin provides partial
response for approximately 10% of cases without evidence of a survival
benefit54 and is considered the standard of care by the United States
Food and Drug Administration (FDA). Importantly, there are no systemic
chemotherapeutic agents that are FDA approved in the United States.
The role of tamoxifen in the treatment of HCC is still under investigation
but a recent meta-analysis showed no benefit.56,57
The medical community faces numerous challenges in HCC and must work
to achieve better management and multidisciplinary care of this complex
disease. Hepatologists are crucial to integrated care, as they are the
specialists most involved in numerous aspects of care including (a)
screening and diagnosis, (b) pre- and post-surgical resection or liver
transplantation management, and (c) care of patients with cirrhotic
and decompensated liver disease. An approach integrating surgical oncology,
diagnostic interventional radiology, gastroenterology, hepatology, radiation
oncology, and medical oncology would greatly benefit patients and physicians
whole, HCC is challenging on many counts. Latent and asymptomatic presentations
make early detection and treatment difficult. Late-stage disease identification
and lack of clinically validated markers create treatment obstacles
and continue to support a poor disease prognosis. Management is further
confounded by the multiple mechanisms leading to cirrhosis and multiple
carcinogenic factors creating complications. Very few patients are suitable
for surgery upon presentation of disease and limited donors are available
to liver transplantation, situations that lead to low overall survival.
The disease confers a high level of tumor recurrence after resection.
Better systemic therapy for nonresectable HCC is greatly needed for
early stages of the disease, including the development of less toxic
agents for patients with liver cirrhosis.
1. Thomas MB, Zhu AX. Hepatocellular carcinoma: the need for progress.
J Clin Oncol. 2005;23:2892-2899.
2. Grieco A, Pompili M, Caminiti G, et al. Prognostic factors for survival
in patients with early-intermediate hepatocellular carcinoma undergoing
non-surgical therapy: comparison of Okuda, CLIP, and BCLC staging systems
in a single Italian centre. Gut. 2005;54:411-8.
3. Bialecki ES, DiBisceglie AM. Clinical presentation and natural course
of hepatocellular carcinoma Eu J Gastroenterol Hepatol. 2005;17:485-489.
4. Del Olmo JA, Serra MA, Rodriguez F, et al. Incidence and risk factors
for hepatocellular carcinoma in 967 patients with cirrhosis. J Cancer
Res Clin Oncol. 1998;124:560-564.
5. Macdonald GA. Pathogenesis of hepatocellular carcinoma. Clin Liver
6. Ogunbiyi JO. Hepatocellular carcinoma in the developing world. Semin
7. El-Serag HB. Epidemiology of hepatocellular carcinoma. Clin Liver
8. Seeff LB. Introduction: the burden of hepatocellular carcinoma. Gastroenterology.
9. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Hepatitis
C infection and the increasing incidence of hepatocellular carcinoma:
a population-based study. Gastroenterology. 2004;127:1372-1380.
10. El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing
increase in the incidence of hepatocellular carcinoma in the United
States: an update. Ann Intern Med. 2003;139:817-823.
11. Bosch FX, Ribes J, Cleries R, Diaz M. Epidemiology of hepatocellular
Clin Liver Dis. 2005;9(2):191-211.
12. Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma.
Gastroenterology. 2004;127(5 suppl):S87-S96.
13. Regimbeau JM, Colombat M, Mognol P, et al. Obesity and diabetes
as a risk factor for hepatocellular carcinoma. Liver Transpl. 2004;10(2,
14. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Diabetes
increases the risk of hepatocellular carcinoma in the United States:
a population based case control study. Gut. 2005;54:533-539.
15. Gish RG, Afdhal NH, Dieterich DT, Reddy KR. Management of hepatitis
C virus in special populations: patient and treatment considerations.
Clin Gastroenterol Hepatol. 2005;3:311-318.
16. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma
in the United States. N Eng J Med. 1999;340:745-750.
17. Koike K, Moriya K, Kimura S. Role of hepatitis C virus in the development
of hepatocellular carcinoma: transgenic approach to viral hepatocarcinogenesis.
J Gastroenterol Hepatol. 2002;17(4):394-400.
18. Moradpour D, Blum HE. Pathogenesis of hepatocellular carcinoma.
Eur J Gastroenterol Hepatol. 2005;17:477-483.
19. Sheu JC, Sung JL, Chen DS, et al. Growth rate of asymptomatic hepatocellular
carcinoma and its clinical implications Gastroenterology. 1985;89:259-266.
20. Borzio M, Bruno S, Roncalli M, et al. Liver cell dysplasia a major
risk factor for hepatocellular carcinoma in cirrhosis: a prospective
study. Gastroenterology. 1995;108:812-817.
21. Pawarode A, Voravud N, Sriuranpong V, et al. Natural history of
untreated primary hepatocellular carcinoma: a retrospective study of
157 patients. Am J Clin Oncol. 1998;21:386-391.
22. Itamoto T, Nakahara H, Tashiro H, et al: Hepatic arterial infusion
of 5-fluorouracil and cisplatin for unresectable or recurrent hepatocellular
carcinoma with tumor thrombus of the portal vein. J Surg Oncol. 2002;80:143–148.
23. Fuchs CS, Clark JW, Ryan DP, et al. A phase II trial of gemcitabine
in patients with advanced hepatocellular carcinoma. Cancer. 2002;94:3186–3191.
24. Nguyen MH, Garcia RT, Simpson PW, Wright TL, Keeffe EB. Racial differences
in effectiveness of alpha-fetoprotein for diagnosis of hepatocellular
carcinoma in hepatitis C virus cirrhosis. Hepatology. 2002;36:410–417.
25. Hayashi K, Kumada T, Nakano S, et al. Usefulness of measurement
of Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein
as a marker of prognosis and recurrence of small hepatocellular carcinoma.
Am J Gastroenterol. 1999;94:3028-3033.
26. Li D, Mallory T, Satomura S. AFP-L3: a new generation of tumor marker
for hepatocellular carcinoma. Clin Chim Acta. 2001;313:15-19. [need
to be confirmed]
27. Sherman M. Pathogenesis and screening for hepatocellular carcinoma.
Clin Liver Dis. 2004;8:419-443.
28. Danta M, Barnes E, Dusheiko G. The surveillance and diagnosis of
hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2005;17:491-496.
29. Ahn J, Flamm SL. Hepatocellular carcinoma. Dis Mon. 2004;50:556-573.
30. Bartolozzi C, Lencioni R, Caramella D, et al. Small hepatocellular
carcinoma. Detection with US, CT, MR imaging, DSA, and Lipiodol-CT.
Acta Radiol. 1996;37:69-74.
31. Durand F, Regimbeau JM, Belghiti J, et al. Assessment of the benefits
and risks of percutaneous biopsy before surgical resection of hepatocellular
carcinoma. J Hepatol. 2001;35:254-258.
32. Yan P, Yan LN. Staging of hepatocellular carcinoma. Hepatobiliary
Pancreat Dis Int. 2003;2:491-495.
33. Marrero JA, Fontana RJ, Barrat A, et al. Prognosis of hepatocellular
carcinoma: comparison of 7 staging systems in an American cohort. Hepatology.
34. McCormack L, Petrowsky H, Clavien P-A. Surgical therapy of hepatocellular
carcinoma. Eur J Gastroenterol Hepatol. 2005;17:497-503.
35. Wildi S, Pestalozzi BC, McCormack L, Clavien PA. Critical evaluation
of the different staging systems for hepatocellular carcinoma. Br J
36. Rilling WS, Drooz A. Multidisciplinary management of hepatocellular
carcinoma. J Vasc Interv Radiol. 2002;13:S259-S263.
37. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet.
38. Roberts LR. Presented at the 5th Annual International Hot Topics
in Liver Disease Conference, Houston, Texas. October 22-23, 2004.
39. Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases
of hepatocellular carcinoma at a Western center. Ann Surg. 1999;229:790–799.
40. Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Intrahepatic recurrence
after curative resection of hepatocellular carcinoma: long-term results
of treatment and prognostic factors. Ann Surg. 1999;229:216–222.
41. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical
treatment for early hepatocellular carcinoma: resection versus transplantation.
42. Arii S, Teramoto K, Kawamura T, et al. Characteristics of recurrent
hepatocellular carcinoma in Japan and our surgical experience. J Hepatobiliary
Pancreat Surg. 2001;8:397–403.
43. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial
lipiodol chemoembolization for unresectable hepatocellular carcinoma.
44. Lau WY, Leung TW, Ho SK, et al. Adjuvant intra-arterial iodine-131-labelled
lipiodol for resectable hepatocellular carcinoma: a prospective randomised
trial. Lancet. 1999;353:797-801.
45. Takai K, Okuno M, Yasuda I, et al. Prevention of second primary
tumors by an acyclic retinoid in patients with hepatocellular carcinoma.
Updated analysis of the long-term follow-up data. Intervirology. 2005;48:39-45.
46. Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy
to lower postsurgical recurrence rates of hepatocellular carcinoma:
a randomised trial. Lancet. 2000;356:802-807.
47. Yao FY, Bass NM, Nikolai B, et al. Liver transplantation for hepatocellular
carcinoma: analysis of survival according to the intention-to-treat
principle and dropout from the waiting list. Liver Transpl. 2002;8:873-883.
48. Brown KA. Liver transplantation. Curr Opin Gastroenterol. 2005;21:331-336.
49. Farnsworth N, Fagan SP, Berger DH, Awad SS. Child-Turcotte-Pugh
versus MELD score as a predictor of outcome after elective and emergent
surgery in cirrhotic patients. Am J Surg. 2004;188:580-583.
50. Wiesner RH, Freeman RB, and Mulligan DC. Liver transplantation for
hepatocellular cancer: the impact of the MELD allocation policy. Gastroenterology.
51. Bruix J, Llovet JM. Prognostic prediction and treatment strategy
in hepatocellular carcinoma. Hepatology. 2002;35:519-524.
52. Gournay J, Tchuenbou J, Richou C, et al. Percutaneous ethanol injection
vs. resection in patients with small single hepatocellular carcinoma:
a retrospective case-control study with cost analysis. Aliment Pharmacol
53. Sala M, Llovet JM, Vilana R, et al. Initial response to percutaneous
ablation predicts survival in patients with hepatocellular carcinoma.
54. Llovet JM, Sala M. Non-surgical therapies of hepatocellular carcinoma.
Eur J Gastroenterol Hepatol. 2005;17:505-513.
55. Raoul JL, Guyader D, Bretagne JF, et al. Prospective randomized
trial of chemoembolization versus intra-arterial injection of 131I-labeled-iodized
oil in the treatment of hepatocellular carcinoma. Hepatology. 1997;26:1156-1161.
56. Lau WY. Management of hepatocellular carcinoma. J R Coll Surg Edinb.
57. Pagliaro L, D'Amico G, Puleo A. Meta-analysis as a source of evidence
in gastroenterology: a critical approach. Ital J Gastroenterol Hepatol.
Safety Profile: The Benefits of Lipophilicity
The chemical properties of lercanidipine include a very high lipophilicity
and membrane partion coefficient that allows a preferential distribution
of the drug into the membranes of smooth muscle cells. This distribution
results in a membrane-controlled kinetics, as opposed to the plasma-controlled
kinetics of most dihydropyridines calcium antagonists, and facilitates
a prolonged pharmacological lowering of blood pressure that lasts 24
hours, despite a short plasma half-life. Lercanidipine displays a sustained
mechanism of action and a significant antihypertensive efficacy when
administered once a day. The onset of its action is gradual. In placebo-controlled
studies involving patients with mild-to-moderate hypertension, lercanidipine
demonstrated a clinically relevant antihypertensive effect. When compared
to other calcium antagonists, lercanidipine demonstrated comparable
efficacy with improved tolerability, most notably a lower incidence
of peripheral edema. Lercanidipine, therefore, represents an improved
option within the class of calcium channel blockers
The clinical relevance of lipophilicity first arose in the late19th
Century, when Hans Horst Meyer and colleagues observed that the ability
of organic anesthetics to inhibit nerve cell function was correlated
with partition function. In effect, Meyer’s seminal lipoid theory
launched what modern drug development refers to today as QSAR (quantitative
structure-activity relationships), linking the nascent science of pharmacology
with biology and clinical medicine. A far cry from observing tadpole
behavior in olive oil, our understanding of partition coefficient today
continues to be influenced by Meyer’s findings, and the main tenets
of his theory remain unchallenged:(1) (1) all lipid-soluble substances
exert a reaction on protoplasm. (2) This reaction is more pronounced
in cells with lipid content that is essential to cell function. And
(3) potency (and arguably clinical safety and efficacy) is related to
a substance’s lipophilic and hydrophilic properties.
of lercanidipine, a highly lipophilic agent, to the next generation
dihydropyridine (DHP) calcium-channel antagonists in the treatment of
hypertension offers a relevant example of the correlation between increased
lipid solubility and improved clinical outcome, in particular, tolerability.
tolerability is desirable in the current treatment of hypertension,
in which long-acting dihydropyridine calcium antagonists lower blood
pressure by the mechanism of powerful vasodilation. This same benefit
is also the cause of the hallmark side effect of these agents: peripheral
edema. While not a life-threatening symptom, ankle edema causes a great
deal of distress to patients and results in a substantial number of
patients becoming non-adherent or discontinuing medication. A dyhydropridine
calcium antagonist that retains potency, while limiting this problematic
side effect would be a welcome addition to the current menu of antihypertensive
medications. Lercanidipine appears to be such an agent. This paper discusses
the unique pharmacokinetic properties of lercanidipine that underlie
its high efficacy and low rate of peripheral edema, compared with other
agents of this class.
A Molecule Designed for Increased Lipophilicity
Lercanidipine is designed with a hydrophobic membrane-soluble “anchor,”
a bulky bis-phenylalkylamine side chain (see figure 1) , making it more
lipophilic than most other drugs in its class. This unique design may
explain how, while other DHP calcium antagonists interact with calcium
channels at a location near the surface of the cell membrane, lercanidipine
appears to interact with the hydrocarbon core of the lipid bilayer,
a feature that can be measured directly as the equilibrium membrane
partition coefficient (Kp[mem] ). Although highly lipid-soluble, the
drug does not readily penetrate the blood-brain barrier due to its bulky
figure 1. Molecular structure of lercanidipine. Must get permission
ionized side-chain facilitates entry into the membrane bilayer of vascular
smooth muscle, lercanidipine diffuses laterally to its specific receptor
site. Distinguishing it from other drugs in its class, lercanidipine’s
pharmacologic activity appears to be controlled by the arterial tissue
wall compartment, rather than the plasma compartment. Lercanidipine
has one of the shortest plasma half-life (approximately 3 hours.) of
all the calcium antagonists.(3) This quick clearance of the plasma compartment
may facilitate accumulation in the smooth-muscle cell membranes where
calcium channels are located. From within the arterial tissue wall compartment,
the drug is stored over a long period of time for gradual interaction
with calcium channels.(3) Thus unlike amlodipine, mimodipine and nitrendipine,
lercanidipine penetrates much deeper into the membrane, achieving an
energetically favorable location, orientation, and conformation for
potentially enhanced activity. Even in comparison with lacidipine, a
sister lipophilic DHP, with a somewhat similar hydrophobic side-chain
on the phenyl moiety, lercanidipine’s protonated amine moiety
imparts unique properties. In fact, lercanidipine’s increased
solubility within the membrane bilayer is thought to confer both a gradual
onset and long duration of action. ,, , (3)
Lercanidipine is absorbed in 2 to 3 hours following administration,
and dmonstrates peak effects up to 30 times later than nitrendipine.(8)
Lercanidipine then undergoes extensive first pass metabolism to largely
inactive metabolites. The extensive distribution profile of lercanidipine
reflects its high lipophilicity. Radioactivity was widely distributed
throughout the body, although concentrations in brain were below the
limit of detection at every sacrifice time (2 h,24 h,96 h,168 h) indicating
that the drug and/or its metabolites did not penetrate the blood-brain
barrier.(5) Elimination of the metabolites occurs via urine and feces,
with little or no recovery of unchanged drug, a finding that is consistent
with its extensive metabolism. (10)
pharmacokinetic properties appear to be dependent on the relative lipophilic/hydrophilic
characteristics. The partition coefficent (Kp[mem] ) is a value expressing
the ratio of the mass of a drug in the lipid membrane and in the aqueous
portion of the cell. For all calcium antagonists, the Kp[mem] is affected
by the cholesterol content of the membrane, which may decrease the drug’s
activity in the cell at higher cholesterol content levels. Another important
parameter is the duration that a drug resides in the membrane, which
is measured by its washout rate (kwo). Further, the wash-in rate (kwi),
a measurement of entry into the membrane and availability for protein
binding, appears to determine the duration of dilation of blood vessels
and lowering of blood pressure.
Lercanidipine has one of the highest known membrane partition coefficients
in its class (See Table 1), and is three orders of magnitude greater
than the corresponding analogue (Rec 2520) after removal of the lipophilic
side-chain.(6.1 vs. 2.4 Log Kp[mem])(3). Because membrane solubility
correlates with duration of action, lercanidipine –– a once-daily
drug that is intrinsically long lasting within the cell ––
has a very long clinical half-life, despite having a very short plasma
half-life. However, its specific lipophilic properties distinguish it
from amlodipine and lacidipine, which have long clinical half-lives.
Amlodipine’s half-life, Kp[mem]=4.3, appears to primarily represent
its activity in the plasma compartment, whereas lercanidipine’s
half-life primarily represents its activity within the arterial endothelium.
In terms of lipophilicity and partition coefficient, lercanidipine is
most similar to lacipidine.
Table 1. Membrane partition coefficients in cardiac model membranes
at aring cholesterol to phospholipid (C:L) mole rations Must get permission
Lercanidipine remains in the membrane compartment for a long period,
also reflecting its longer duration of action. Herbette and colleagues(3)
studied Lercanidipine’s washout rates to measure the ability of
the drug’s membrane-transport kinetic capability, and reported
that lercanidipine’s washout rate was 40%–80% slower than
that of lacidipine, which has the slowest rate measured to date. This
slow washout rate signifies that the partitioned lercanidipine resides
in the membrane bilayer for a longer period than lacidipine, and thus
all other calcium antagonists.
It has been hypothesized that the particular lipophilic property of
a slow washout rate combined with a high partition coefficient explains,
at least in part, a high tolerance to membrane cholesterol.(3) The level
of cholesterol within calcium channels appears to affect the binding
of calcium antagonist to cell membranes. The presence of increasing
amounts of cholesterol in cell membranes decreases the concentration
of calcium antagonists within the bilayer compartment. The concentration
of nimodipine, for example, is decreased 11-fold when membrane cholesterol
increased from 0:1 to 0.6:1 cholesterol: phospholipid molar ratio. The
concentration of lacidipine, the second most lipophilic of the calcium
antagonists following lercanidipine, appears also to be dependent on
the cholesterol level in target membranes, which can vary widely in
cardiac and vascular tissues, especially with progressive atherosclerosis.
Thus, lercanidipine, with its dual lipophilic properties of high partition
coefficient and slow washout rate, may exhibit reduced sensitivity to
changes in membrane cholesterol levels.(6,3)
Lercanidipine has a gradual onset of action with plasma concentration
reaching peak levels at about 3 hours.(10) This phenomenon is due to
the drug’s inherent physicochemical properties, rather than on
a slow release devise, as is the case with previous generations of calcium
antagonists. When given orally, lercanidipine appears to have a longer
hepatic transfer time before reaching peak plasma levels, than other
calcium antagonists with the exception of amlodipine. First-generation
calcium antagonists demonstrated a rapid onset of vasodilator antihypertensive
action, leading to sympathetic activation and reflex tachycardia, thus
these agents are no longer used clinically. Nimodipine, nitrendipine,
and nifedipine rapidly reached peak plasma concentration in less than
2 hours and peak activity with respect to smooth-muscle cell relaxation
and vasodilation with a similar time course. (3) Additionally, these
early drugs had very rapid equilibration times (Kpmem = 3), rapid washout
rates, and easy transport across membranes. The combination of a short
plasma half-life and a rapid onset of action can produce elevated side-effects,
including headaches, nausea, ankle edema and flushing. Lercanidipine,
with its relatively short plasma half-life, gradual onset of action
and long duration of action may be indicative of its good safety profile.
Lercanidipine, at a single daily dose, exerts a prolonged antihypertensive
action lasting 24 hours, as shown by measuring blood pressure in all
pivotal studies at trough (24-hours-, post-dose), and by an ambulatory
blood pressure monitoring in placebo-controlled studies. The drug has
a gradual onset of blood pressure lowering activity with a smooth decrease
in pressure over 24 hours.(10) Ambrosioni and colleagues conducted two
ambulatory blood pressure monitoring (ABPM) studies to define the antihypertensive
activity of lercanidipine. In the first study, three parallel groups
of eight patients each were treated with a single daily dose of 5-,
10- or 20-mg lercanidipine tablets for 4 weeks after a 3-week placebo
run-in period, and found that the trough-to-peak ratio was greater than
0.6 with doses of both 10 and 20 mg/day. No significant changes in heart
rate were observed. In the second study, 20 patients were enrolled in
a cross-over design, treated with single doses of 10 and 20 mg lercanidipine
capsules, with each active treatment day preceded and followed by 3
and 2 weeks of placebo, respectively. The results showed that single
20-mg dose significantly decreased blood pressure for 24 hours, whereas
single 10 mg dose reduced blood pressure only during the day.
randomized, double-blind, placebo-controlled studies comparing the efficacy
of lercanidipine with that of placebo and of other antihypertensive
agents in the treatment of patients with mild-to-moderate hypertension
have been reported. At recommended dosages, lercanidipine has been shown
to be as effective as amlodipine, atenolol, captopril, slow release
nifedipine, nitrendipine, nifedipine GITS, losartan, enalapril, and
candesartan cilexetil. Further, lercanidipine has been shown to have
no significant effect on heart rate, cardiac function or atrioventiricular
conduction.(16), , In patients with angina, it does not induce an increase
in heart rate or double product (heart rate x blood pressure), either
at rest or during exercise. ,
at a 10 mg dosage once daily to 133 elderly patients aged 60 to 85 years
with mild to moderate hypertension, lercanidipine significantly reduced
mean diastolic blood pressure compared with placebo (response rate 59%).(27)
Titration to 20 mg/day after 4 weeks in non responders increased the
response rate to 87.5% at week 8; only 11 of 88 lercandidipine recipients
required titration to 30 mg/day for BP control. Babagallo and colleagues
studied 70 elderly patients (mean age 67 years) with isolated systolic
hypertension, and found that lercanidipine 10 or 20 mg once daily for
8 weeks reduced systolic blood pressure significantly compared with
placebo (-32.4 vs 9.6 mm Hg; p< 0.001).
studies indicate that lercanidipine is an effective, long-acting drug
that does not demonstrate reflex cardiostimulation, with efficacy comparable
to a variety of second and third generation calcium antagonists, as
well as to a range of agents from other antihypertensive drug classes.
Lercanidipine has demonstrated a good tolerability profile in several
placebo-controlled, randomized studies. Testa and colleagues(11) pooled
and reviewed all data concerning the safety profile and adverse events
of lercanidipine from a safety database of 1799 patients. The evaluation
is based on 1317 patients who received lercanidipine, 156 of whom experienced
adverse events (12%), in comparison with 16/277 (7%) of placebo-treated
patients. In the majority of cases, these events were classified as
mild-to moderate in severity and are shown below in Table 2. A lower
incidence of events occurred with the 10 mg dose, particularly tachycardia
(0.62% lercanidipine vs. 0.44% placebo) and peripheral edema (0.89%
lercanidipine and 1.32% placebo). With 20 mg titrated lercanidipine
the incidence was 4.13% for tachycardia and 1.96% for peripheral edema.
Thus, at the 20 mg dose, lercanidipine has a similar incidence of pedal
edema as does placebo.
Table 2. Most commonly reported Adverse Events (Aes) in each treatment
group by different system/organ class. Must get permission from Testa
second generation calcium antagonists have been reported to induce side-effects
responsible for treatment withdrawal or treatment replacement. , , ,
The lipophilic design of lercanidipine, with its gradual onset rate
correlating to a gradual lowering of blood pressure, appears to reduce
the incidence of usual vasodilatory-related event and peripheral edema.
As noted above, in several clinical studies, the incidence of ankle
edema associated with lercanidipine treatment was found to be broadly
comparable to that associated with placebo, based upon patient subjective
reports.(11),(21), , In relation to the symptom of peripheral edema,
subjective reports generally correlate well with patient adherence to
medication; however, two recent well-designed studies were conducted
to verify objectively lercanidipine’s comparatively low reported
incidence of ankle edema.
and colleagues(23) compared the effect of lercanidipine to nifedipine
GITS on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure
(PSTP), which are considered objective measures of calcium antagonist-induced
ankle edema. After a 4-week placebo run-in period, patients were randomly
assigned to lercandidipine 10 mg once daily or nifedipine GITS 30 mg
once daily for 12 weeks in a randomized, double-blind, parallel-group
trial. In the sixty patients (34 men and 26 women), lercanidipine and
nifedipine GITS produced similar reduction s in systolic and diastolic
blood pressure (lercanidipine, -18.7/11.8 mmHg; nifedipine GITS, -18.8/11.5
mm Hg (P<,0.001 vs placebo). However, lercanidipine produced a significantly
less pronounced (p<0.001) increase in AFV (143.6mL) and PSTP (0.9
cm H2O) compared with nifedipine GITS (AFV, 284.2 mL; PSTPS, 1.8 cm
Leonetti and colleagues conducted a large, long-term study to assess
the comparable tolerability of lercanidipine, compared with amlodipine
and lacidipine. In this multi-center, double-blind, parallel group study
of 828 elderly hypertensives, patients were randomized to receive 10-mg
lercanidipine, 5-mg amlodipine or 2-mg lacidipine given once daily for
4 weeks following a 2-week wash-out period. Treatment lasted from a
minimum of 6 months to a maximum of 2 years. The incidence of peripheral
edema was substantially higher for amlodipine (19%) than for lercanidipine
(9.3%) and its lipophilic sister-drug lacipidine (4.3%). Intensity of
edema was in most cases judged as mild for lercanidipine and moderate
for amlodipine and lacidipine. The percentage of patients withdrawn
for peripheral edema was significantly greater (p,0.001) in the amlodipine
group (8.5%) than in the lercanidipine (2.1%) and lacidipine (1.4%)
group. The authors hypothesize that lipophilicity may help in favoring
binding of lercanidipine to the few calcium channels located on vein
smooth muscle cells, supported by the fact that lercanidipine and lacidipine
shared a similar tolerability profile, compared to amlodipine.
appears to be a reliably tolerable calcium antagonist with lower incidence
of peripheral edema, compared to its less lipophilic counterparts.
Lercanidipine is the first lipophilic dihydropyridine calcium antagonist
soon to be approved in the United States, though other experimental
agents with similar lipophilic properties are under development. The
drug’s unique design gives it a long duration of action and a
slow onset of effect, for once daily dosing. Clinical trials have shown
statistically significant reductions in both systolic and diastolic
blood pressure with lercanidipine, relative to placebo, and comparable
to amlodipine, atenolol captopril slow release nifedipine preparations,
nitrendipine, losartan, enalapril, and candesartan cilexetil. Lercanidipine
is similar or superior to these agents in tolerability, with a significantly
lower incidence of ankle edema than other calcium antagonists.
1. Lipnick, RL. Special Feature: Hans Horst Meyer and the lipoid theory
of narcosis. TiPS :265-269, 1989.
2. Faemer KC, Jacobs EW, Phillips CR. Long-term patient compliance with
prescribed regimens of calcium channel blockers. Clin Ther. 1995
3. Herbette LG, Vecchiarelli M, Sartani A, et al. Lercanidipine: short
plasma half-life, long duration of action and high cholesterol tolerance.
Blood Pressure 1998;7(suppl 2):10-17.
4. Herbette LG, Rhodes DG, Mason RP. New approaches to drug design and
delivery based on drug-membrane interactions. Drug Design Delivery 1991;7:75-118.
5. Farina P, Targa G, Leoni B, et al. Pharmacokinetics of lercanidipine
in animals. II. Distribution to and elimination from organs and tissues
after administration of [14C]lercanidipine to rats and dogs.Whole-body
autoradiography, biliary excretion and enterohepatic circulation and
biotransformation in rats. J Cardiovasc Pharmacol 1997;29(suppl 1):S97-S108.
6. Rhodes DG, Sarmiento JG, Herbette LG. Kinetics of binding of membrane-active
drugs to receptor sites. Diffusion limited rates for a membrane bilayer
approach of 1,4-dihydropyridine ca+2 channel antagonists to their active
site. Mol Pharmacol 1985;27:612-23.
7. Herbette LG, Mason PE, Gaviraghi, G, Tulenko TN and Mason RP. The
molecular basis for lacidipine’s unique pharmacokinetics: optimal
hydrophobicity results in membrane interactions that may facilitate
the treatment of atherosclerosis. J Card Pharma 1994;23(suppl 5):S16-S25.
8. Gasser R, Koppel H, Klein W. Lercanidipine, a new third generation
Ca-antagonist in the treatment of hypertension. J Clin Basic Cardiol
9. Leonardi A, Motta G, Pennini R, et al. Asymmetric N-(3,3-diphenylpropyl)
aminoalkyl esters of 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic
acids with anytihypertensive activity. Eur J Med Chem 1998;33:339-420.
10. Barchelli M, Dolfini E, Farina P, et al. Clinical pharmacokinetics
of lercanidipine. J Cardiovasc Pharmacol 1997;29 (suppl 1):S97-S109.
11. Testa R, Leonardi A, Tajana A, et al. Lercanidipine (rec 15/2375):
A novel 1,4-dihydropyridine calcium antagonist for hypertension. Card
Drug Rev 1997;15(3):187-129.
12. Abernethy DR, Gutkowaka J, Winterbottom LM. Effects of amlodipine,
a long acting dihydropridine calcium antagonist in aging hypertension:
pharmacodynamics in relation to disposition. Clin Pharmacol Ther 1990;48:76-86.
13. Mason RP, Moisey DM, Shajenko L. Cholesterol alters the binding
of ca2+ channel blockers to the membrane lipid bilayer. Mol Pharmacol
14. Herbette LG, Mason PE, Sweeney KR, et al. Favorable amphiphilicity
of nimodipine facilitates its interactions with brain membranes. Neuropharmacology
15. Tulenko TN. Atherogenic activity of excess membrane cholesterol
in arterial smooth muscle and endothelial cell.s J Am Coll Cardiol 1991;17:24A.
16. Faulkner JK, McGibney D, Chasseaud LF, et al. The pharmacokinetics
of amlodipine in healthy volunteers after single intravenous and oral
doses and after repeated oral doses given once daily. Brit J Clin Pharmacol
17. Ambrosioni E, Circo A. Activity of lercanidipine administered in
single and repeated doses once daily as monitored over 24 hours in patients
with mild to moderate essential hypertension. J Cardiovasc Pharmacol
1997;29 (suppl 2):S16-S20.
18. Ambrosioni E and Circo A. Activity of lercanidipine administered
in single and repeated doses once daily as monitored over 24 hourse
in patietns with mild to moderate essential hypertension. J Cardiovasc
Pharmacol 29 (Suppl 2):S16-S20.
19. De Giorgio LA, Orlandini F, Malasoma P, et al. Double-blind crossover
study of lercanidipine versus amlodipine in th etreatment of mild-to-moderate
essential hypertension. Curr Ther Res 1999;60:511-520.
20. Morisco C, Trimarco B. Efficacy and tolerability of lercanidipine
in comparison to and in combination with atenolol in patients with mild
to moderate hypertension in a double-blind controlled study. J Cardiovasc
Pharmacol 1997;29(Suppl 2):S26-S30.
21. Barbagallo Sangiorgi G, Putignano E, et al. Efficacy and tolerability
of lercanidipine vs. captopril in patients with mild to moderate hypertension
in a double –blind controlled study. J Cardiovasc Pharmacol 1997;29
22. Policicchio D, Magliocca R, Malliani A. Efficacy and tolerability
of lercanidipine in patients with mild to moderate essential hypertension:
a comparative study with slow-release nifedipine. J Cardiovasc Pharmacol
1997;29 (Suppl 2):S31-S39.
23. Rengo F, Romis L, Activity of lercanidipine in double-blind comparison
with nitrendipine in combination treatment of patients with resistant
essential hypertension. J Cardiovasc Pharmacol 1997:29 (Suppl2):S54-S58.
24. Fogari R, Malamani GD, Zoppi A, et al. Comparative effect of lercanidipine
and nifedipine gastrointestinal therapeutic system on ankle volume and
subcutaneous interstitial pressure in hypertensive patients: a double-blind,
randomized, parallel-group study. Curr Ther Res 2000:61:850-862.
22. Fogari R, Mugellini A, Corradi L, et al. Efficacy of lercanidipine
vs losartan on left ventricular hypertrophy in hypertensive type 2 diabetec
patients [abstract]. J Hypertens 2000;18(Suppl 2):S65.
23. Sanchez Gomez A, Sayans Gomez R, Alvarez JL, et al. Left ventricular
hypertrophy regression after antihypertensive treatment with lercanidipinevs
enalapril [abstract]. Presented at the 5th National Meeting of Spanish
Society of Hypertension; March 7-10, 2000;Madrid, Spain.
24. Arnada P, Arnada FJ, Bianchi JL, et al. Therapeutic effacacy and
tolerability of lercanidipine versus candesartan, alone or in combination,
in mild-moderate essential hypertensives [abstract]. J Hypertens 2000;18
25. Ninci MA, Magliocca R, Malliani A. Efficacy and tolerability of
lercanidipine in elderly patients with mild to moderate hypertension
placebo-controlled double-blind study. J Cardiovasc Pharmacol 1997;29(Suppl
26. Omboni S, Zanchetti A, for the Multicenter Study Investigators.
Antihypertensive efficacy of lercanidipine at 2.5,5 and 10 mg in mild
to moderate essential hypertensives assessed by clinic and ambulatory
blood pressure measurements. J Hypertens 1998;16:1831-1838.
27. Specchia G, Saccaggi SP, Ghezi C. Cardiovascular safety of lercanidipine
in patients with angine pectoris: a review of six randomized clinical
trials. Curr Ther Res 2001:62:3-15.
28. Acanfora D, Gheorghiade M, Rotiroti D, et al. Acute dose-response,
double-blind, placebo-controlled pilot study of lercanidipine in patients
with angina pectoris. Curr Ther Res 2000;61:255-265.
29. Barbagallo M, Barbagallo Sangiorgi G. Efficacy and tolerability
of lercanidipine in monotherapy in elderly patients with isolated systolic
hypertension. Aging Clin Exp Res. (In press, should be published by
30. Guidelines Subcommittee of the World Health Organization-International
Society of Hypertension (WHO-ISH) Mild Hypertension Liaison Committee.
1999 World Health Organization-International Society of Hypertension
Guidelines for the Management of Hypertension. J Hypertens 1999;17:151-183.
31. Zanchetti A. Current position of calcium antagonists in hypertension.
J Hypertens 1996;14 (Suppl 3):S11-S15.
32. Luscher TF, Cosentino F. The classification of calcium-antagonists
and their selection in the treatment of hypertension. A reappraisal.
33. Ambrosioni E, Leonetti G, Pessina AC, et al. Patterns of hypertension
management in Italy: results of a pharmacoepidemiological survey on
antihypertensive therapy. J Hypertens 2000;18:1691-1699.
34. Leonetti G. The safety profile of antihypertensive drugs as the
key factor for the achievement of blood pressure control: Current experience
with lercanidipine. High Blood Press 1999;8:92-101.
35. Meredith PA. Lercanidipine: a novel lipophilic dihydropyridine calcium
antagonist with long duration of action and high vascular selectivity.
Exp Opin Invest Drugs 1999;8:1043-1062.
36. Leonetti G, Magnani B, Pessina AC, et al. Tolerability of long-term
treatment with lercanidipine vs. amlodipine and lacidipine in elderly
hypertensives. Am J Hypertens (In press).
>>Return to TOP
the Clinical Paradigm: Treating Systolic Blood Pressure to Goal
major concern with hypertension management relates to a general lack
of physician awareness concerning the critical role systolic blood pressure
control plays in preventing cardiovascular disease events. The robust
relationship between systolic blood pressure and both stroke and heart
attack has long been established. Nonetheless, there appears to be an
historical reluctance to change the clinical paradigm to include treating
systolic blood pressure to goal. Several well-designed, double-blind,
placebo-controlled trials have demonstrated that both multi-drug regimens
and newer monotherapy agents provide aggressive control in elderly patients
with isolated systolic hypertension –– without increasing
side effects. Felodipine, amlodipine, and the new long-lasting dihydropyridine
calcium antagonist, lercanidipine, have demonstrated impressive results
controlling systolic blood pressure, even in hard-to-control patients.
As such effective agents continue to become available on the market,
a concerted effort to educate physicians concerning the benefits of
treating all patients to systolic goal must be waged.
Hypertension is a major risk factor in the development of stroke, congestive
heart failure, coronary heart disease, peripheral vascular disease and
renal failure. With nearly 50 million hypertensive individuals in the
United States (Kannel.1995), the alarming, persistent rate of uncontrolled
blood pressure remains troubling. New data link poor systolic blood
pressure control to a poor rate of overall control to goal (< 140
mm HG systolic and < 90 mm Hg diastolic) [Lloyd-Jones, 2000] and
echo other persuasive evidence that cardiovascular risk is more closely
associated with systolic than diastolic pressure (He, 1999). As long
ago as three decades, the Framingham Heart study showed that at any
given diastolic pressure level, systolic pressure is related to increased
risk for patients over 50 (Kannel, 1971). Together, these data suggest
that the traditional clinical paradigm emphasizing control of diastolic
blood pressure, to the exclusion of systolic blood pressure control,
may indeed contribute to the fact that only 27% of hypertensive Americans
attain blood pressure control (JNC VI), with notably poor outcomes in
the elderly. This paper will review evidence that systolic blood pressure
has long been recognized as a powerful, reversible determinant of cardiovascular
risk, a phenomenon that has yet to be addressed adequately in clinical
of Blood Pressure Trends: Systolic vs. Diastolic
Since the invention of the Riva-Rocci cuff in 1896, clinical practice
has benefited from the rapid, reproducible measurements of systolic
blood pressure(Riva-Rocci, 1896). In fact, thanks to careful study a
century ago, systolic pressure above 140 mm Hg was well known to be
associated with a three-fold increase in mortality (Postel-Vinay, 1996).
Because the ability to influence high blood pressure had not yet caught
up with the ability to measure it, individuals demonstrating high systolic
pressures at the turn of the century were considered a poor insurance
risk and routinely denied coverage. By 1909, 22 of 32 U.S. insurance
companies recommended measuring systolic blood pressure (Postel-Vinay,
1996) and made careful note to record mortality among hypertensive insurance
policy holders. Clinical practice, however, soon veered from the evidence
of this trend, and clinicians began to focus on diastolic blood pressure,
which at the time was much-less widely studied. In 1926, somewhat inexplicably,
Halls Daly began to write disparagingly of systolic pressure alone as
a predictor of coronary outcomes (Swales, 2000), and to focus instead
on diastolic pressure, basing his argument on a loose interpretation
of pathophysiology (Halls Dally, 1926).
toward favoring diastolic over systolic blood pressure control persisted
throughout the 1920's and 1930's, championed by several of Halls Daly's
most esteemed colleagues (Rollerston, 1928; Fishberg, 1931) thus establishing
a new medical authority. As effective blood-pressure lowering agents
subsequently became available, end-point trials were designed with exclusive
diastolic criteria for recruitment (Swales, 2000), thus codifying the
20th Century the notion of diastolic pressure as the predominant risk
in hypertension. Despite the fact that the 1971 Framingham data demonstrated
the greater predictive value of systolic pressure for cardiovascular
disease, the case for systolic blood pressure continued to meet with
considerable opposition (Ramsey, 1986). In fact, in 1977 the first Joint
National Committee on the Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure (JNC) report defined diastolic blood pressure
as the basis for detection and treatment (JNC, 1977). Systolic hypertension,
due to hardening and loss of elasticity of the major arteries, was held
as an unavoidable consequence of aging, as opposed to diastolic blood
pressure, long considered a function of increased peripheral resistance
years after the Framingham Study and other reports supporting evidence
that a reduction of systolic blood pressure correlates with reduced
morbidity and morality, JNC-V finally acknowledged that systolic blood
pressure can also be used to define individuals as hypertensive (JNC,
1993). Moreover, studies have recently and repeatedly demonstrated that
higher pulse pressure is proportionate to greater cardiovascular risk,
an important finding because increased pulse pressure is primarily related
to increased systolic pressure (O’Rourke, 1999). Further, antihypertensive
regimens that successfully lower diastolic blood pressure without adequately
lowering systolic blood pressure can result negatively in increased
Benefits of Systolic Blood Pressure Control
The relationship between systolic blood pressure and cardiovascular
disease is particularly important for patients with isolated systolic
hypertension, defined as ≥ 140 mm HG, < 90 mm Hg. As it stands
today, isolated systolic hypertension is the most common form of hypertension
in older patients and the least likely to be treated (Sagie, 1993).
In multiple drug therapy, older patients may experience more serious
side effects and mistaken dosages (Williamson, 1980). Studies using
calcium channel blockers as monotherapy in older patients with isolated
systolic hypertension have shown impressive outcomes. However, these
data my be applicable beyond the elderly and patients with isolated
systolic hypertension. In fact, in a clinical advisory statement by
Izzo and colleagues state that the National High Blood Pressure Education
Program now recommends that systolic blood pressure become “the
major criterion for diagnosis, staging, and therapeutic management of
hypertension, particularly in middle-aged and older Americans (Izzo,
for treating systolic blood pressure can be found in two seminal studies,
which offer compelling supportive data. The SHEP Trial was a double-blind,
randomized, placebo-controlled study of 4,736 persons over the age of
60, who had Stage 2 or 3 isolated systolic hypertension (systolic blood
pressure ≥ 160 mm HG and diastolic blood pressure < 90 mm Hg
(SHEP, 1991). At randomization, the average pressures were 170 mm HG
systolic and 77 mm HG diastolic Average follow-up was 4.5 years with
a primary outcome measure of fatal and non-fatal stroke. Patients were
randomized to either the placebo or active treatment group of low-dose
chlorthalidone 12.5 mg, titrated to 25 mg if goal systolic blood pressure
was not met (goal was <160 mm Hg for study subjects with baseline
at > 180 mm Hg and a reduction of ≥ 20 mm HG for study subjects
with a baseline between 160-179 mm Hg). Atenolol 25 mg was used if goal
was not met at maximal dose of chlorthalidone. Reserpine (0.05 mg/d)
was given when atenolol was contraindicated. At the completion of the
study, the average blood pressure was 143/68 mm HG in the active treatment
group and 155/73 mm HG in the placebo group with placebo-corrected reductions
of 12/5 mm HG. The five-year incidence of total stroke rate was 5.2/100
for active therapy and 8.2/100 for placebo. Additionally, those study
subject randomized to treatment had marked reductions in myocardial
infarction (27%), heart failure (55%), and stroke (37%) as well as exhibiting
trends toward improvement in depression and dementia scores. A large
randomized European trial of isolated systolic hypertension (Syst-EUR)
found reductions in systolic blood pressure and cardiovascular outcomes
similar to those in SHEP (Staessen, 1999). Cardiovascular endpoints
and mortality were all significantly reduced when systolic blood pressure
was lowered by 20 mm Hg in study subjects > 60 years of age.
The medical community appears to be reluctant to embrace a paradigm
shift toward emphasizing systolic blood pressure, despite renewed efforts
and data to demonstrate the benefits of such a shift. The most recent
guidelines of the World Health Organization /International Society of
Hypertension (WHO/ISH) [Guidelines Subcommittee, 1999] and JNC VI (JNC,
1997) recommend treating systolic blood pressure to goal. Both committees
concluded that the higher stage (in JNC VI) or grade (in WHO/ISH) should
be considered to be the strata in which the patient belongs. Further,
systolic blood pressure has emerged as the second single greatest risk
factor after age for cardiovascular disease (Wilking, 1988). And yet
there is a clear lack of awareness on the part of the physician. In
2000, a population sample survey and visit-level analysis indicated
that when diastolic blood pressure was >90 m Hg, physicians intensified
drug therapy 24% of the time. However, when systolic pressure was >
140 mm Hg, they intensified therapy in only 4% of visits (Hyman, 2000)
It is likely that the primary care community will need to identify and
address the dynamics of our failure to control systolic blood pressure.
physicians seem to appear to be especially reluctant to treat older
patients to goal, perhaps because of concerns about greater risk of
side effects, specifically posteral hypotension (Burt, 1995), it will
be important to educate and motivate physicians to use antihyptensive
drugs that effectively lower systolic blood pressure.
Treating Isolated Systolic Hypertension to Goal
Chronic thiazide diuretics and calcium channel blockers have been shown
to decrease cardiovascular morbidity and mortality by lowering systolic
blood pressure and pulse pressure (SHEP and Straessen). There are several
factors involved in treatment selection. With the exception of congestive
heart failure due to poor systolic function, few associated conditions
are likely to be made worse by treatment of hypertension with a long-acting
calcium channel blocker (Black, 1990). Whereas several previous large
trials have failed to show a difference in outcome in part due to poor
separation between the blood pressures achieved in the randomized groups
(Lazarus, 1997; Hansson, 1998; Estacio, 2000), recent studies have demonstrated
that blood pressure can be controlled to goal with a variety of agents
in a number of highly resistant populations.
American Study of Kidney Disease and Hypertension (AASK) demonstrated
the feasibility of achieving lower than usual systolic blood pressure
in a high-risk population (Wright, 2002). AASK evaluated the effect
of blood pressure and choice of antihypertensive drug on the rate of
renal function decline. The randomized controlled trial included 1094
African American patients with hypertensive nephrosclerosis and without
diabetes, who were randomized to one of two set goals (102 –107
mm Hg or ≤ 92 mm Hg). Study subjects were randomized to metoprolol,
ramipril, or amlodipine, and additional agents were added, as required,
in the following recommended order: furosemide, doxasozin, chonidine,
hydralazine or minoxidil. The percentage of study subjects randomized
to the lower goal who achieved a blood pressure of less than 140/90
mm Hg increased from a baseline of 20% to 78% after 14 months of treatment.
The percentage of study subjects randomized to the usual goal increased
from 21% to 41%. Blood pressure reduction was similar regardless of
age, sex, body mass index, education, insurance/employment status, income
or marital status. These results proved that adequate blood pressure
control could be achieved even in the most difficult-to-control hypertensive
populations. The average number of agent required to reach blood pressure
goal was approximately 3 agents. This is similar to findings in other
trials, regardless of hypertensive severity (Hansson, 1998; Levy, 1998;
UK Prospective Diabetes Study Group, 1998). Further, there was no evidence
of increased drug-related symptoms or hypertension, whether comparing
incidence of adverse symptoms between usual and low goal groups or examining
reports of participants within randomized groups whose blood pressure
above goal, at goal, or below goal.
As potent vasodilators, calcium channel blockers are particularly effective
at lowering systolic blood pressure, treating patients with isolated
systolic hypertension and the elderly (JNC VI). In a one-year double-blind
study comparing felodipine (2.5, 5, or 10 mg once daily) to placebo
in patients ≥ 55, stage 1 isolated systolic hypertension was defined
as systolic blood pressure between 140 and 159 mm Hg (Black, 2001).
During 52 weeks of treatment, patients randomized to active treatment
achieved significantly lower blood pressure (123.0 +/- 11.7/80.2 +/-
7.6 mm Hg for extended-release Felodipine versus 147.5 +/- 16.0/83.5
+/- 9.7 mm Hg for placebo, P<0.01 for each). These data are the first
from a placebo-controlled, one-year clinical trial to show that pharmacological
treatment in patients with stage 1 isolated systolic hypertension is
effective, safe, well-tolerated, and associated with beneficial effects
and quality of life. The data from this study has been interpreted as
an encouragement to physicians and patients to use effective antihypertensive
agents to control systolic blood pressure (Izzo, 2000).
channel blockers are recognized to be effective at lowering systolic
blood pressure, they have been associated with peripheral edema, in
some cases limiting compliance to treatment. Newer calcium channel blockers
may prove to be better tolerated. Eighty-three patients with isolated
systolic hypertension were enrolled in a multicenter, double-blind,
randomized, placebo controlled study to investigate the efficacy and
tolerability of lercanidipine, a new long-lasting dihydropiridine calcium
antagonist (Barbagallo, 2000). After wash-out and placebo run-in periods,
patients were randomly assigned to placebo or lercanidipine (10 mg daily)
treatment for 4 weeks. Non-responding treatment patients were later
treated with 20 mg of lercanidipine once daily for an additional 4 weeks.
At the end of the study, the reduction in systolic blood pressure was
significantly larger in patients treated with lercanidipine (32.4 mm
Hg) compared to the placebo (9.6 mm Hg). Diastolic blood pressure decreased
slightly, and to a significant level in patients treated with lercanidipine.
Treatment was well tolerated with a the incidence of peripheral edema
in treated patients comparable to placebo. At the end of the treatment
phase, 23 of 37 patients (62%) were normalized. Thus, this study indicates
that lercanidipine, used as monotherapy once daily is effective in lowering
elevated systolic blood pressure in the elderly.
In the treatment of hypertension, poor control is correlated with a
lack of systolic blood pressure control. Several studies have demonstrated
that multi-drug regimens, and even monotherapy with calcium antagonists,
can be aggressively used to reduce systolic blood pressure, and thus
cardiovascular disease events. Therefore, greater efforts need to be
made to increase clinician awareness concerning achieving goal systolic
pressure levels in hypertensive patients. Newer calcium channel blockers,
including lercanidipine, give hope that systolic blood pressure can
be normalized within the general hypertension populations, as well as
in more traditionally hard-to-treat patients.
Barbagallo M and Barbagallo Sangiorgi G. Efficacy and tolerability of
lercanidipine in monotherapy in elderly patients with isolated systolic
hypertension. Aging Clin Exp Res. 2000;12:375-379.
Black HB. Therapeutic considerations in the elderly hypertensive: The
role of calcium channel blockers. Am J Hypertens 1990;3:347S:354S.
Black HR, Ellit WJ, Weber MA, et al. One-year study of felodipine or
placebo for stage 1 isolated systolic hypertension. Hypertension 2001;38:1118-1123.
Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in
the US adult population: results from the Third National Health and
Nutrition Examination Survey 1988-1991. Hypertension 1995;25:305-313.
Estacio RO, Jeffers BW, Gifford N, et al Effect of blood pressure control
on diabetic microvascular complications in patients with hypertension
and type 2 diabetes. Diabetes Care. 2000;23(Suppl 2):B54-B64.
Fishberg AM. Hypertension and Nephritis. 2nd Edition. Lea and Febiger:
Guidelines Subcommittee, World Health Organization-International Society
of Hypertension Guidelines for the management of hypertension. J Hypertens
Halls Dally JF. High Blood Pressure: Its Variations and Control. William
Heinemann (Medical Books); London, 1926.
Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood
pressure lowering and low dose aspiring in patients with hypertension:
principal results of the Hypternsion Optimal Treatment (HOT) randomized
trial. Lancet. 1998;351:1755-1762.
He J, Whelton PK. Elevated systolic blood pressure as a risk factor
for cardiovascular and renal disease. J Hypertens 1999; 19 (suppl 2)
Hyman DJ, Pavlik VN, Vallbona C. Physician role in lack of awareness
and control of hypertension. J Clin Hypertens 2000;2:324-330.
Izzo JL Jr, Levy D, Black HR. Importance of systolic blood pressure
in older Americans. Hypertension. 2000;35:1021-1024.
Kannel WB, Gordon T, Schwartz MJ. Systolic versus diastolic blood pressure
and risk or coronary heart disease: Framingham study. Am J Cardiol 1971;27:335-345.
Kannel WB. Coronary risk factors: an overview. In: Willerston, Cohn
JN, eds. Cardiovascular Medicine. New York, NY: Churchill Livingstone;
Lazarus JM, Bourgoignie JJ, Buckalew VM, et al. For the Modification
of Diet in Renal Disease Study Group. Achievement and safety of a low
blood pressure goal in chronic renal disease. Hypertension. 1997;29:41-650.
Levy AS, Beto JA, Coronado BE, et al., for the National Kidney Foundation
Task Force on Cardiovascular Disease. Controlling the epidemic of cardiovascular
disease in chronic renal disease: what do we know? What do we need to
learn? Where do we go from here? Am J Kidney Dis 1998;32:853-906.
Lloyd-Jones DM, Evans JC, Larson MG, et al. Differential control of
systolic and diastolic blood pressure: factors associated with lack
of blood pressure control in the community. Hypertens 2000;36:594-599.
O’Rourke M, Frohlich ED. Pulse pressure: is this a clinically
useful risk factor? Hypertension 1999;153:154-183.
Postel-Vinay N. A Century of Arterial Hypertension. 1896-1996. Chichester,
John Wiley and Sons/Imotherp, 1996.
Ramsay LE, Waller PC. Strokes in mild hypertension: diastolic rules.
Lancet 1986; 2:1349-1350.
Report of the Joint National Committee on Detection, Evaluation, and
Treatment of High Blood Pressure: a cooperative study. JAMA 1977;237:25-261.
Riva-Rocci S. Un Nuovo Sfigmomanometro. Gazzetta Medica di Torino 1896;
Rolleston HP. Cardiovascular disease since Harvey's discovery. The Harveian
Oration 1928. Cambridge University Press; Cambridge, 1928.
Sagie A, Larson MG, Levy D. The natural history of borderline isolated
systolic hypertension. N Engl J Med 1993;329:1912-1917.
SHEP Cooperative Research Group. Prevention of stroke by antihypertensive
drug treatment in older persons with isolated systolic hypertension.
Final results of the Systolic Hyptertension in the Elderly Program (SHEP).
JAMA 1991; 265:3255-3264.
Staessen JA, Thijs L, Fagard R, et al. Predicting cardiovascular risk
using conventional vs ambulatory blood pressure in older patients with
systolic hypertension: Systolic Hypertension in Europe Trial Investigators.
Swales JD. Systolic versus diastolic pressure: paradigm shift or cycle?
J Human Hypertens 2000;14:477-479.
The Fifth Report of the Joint National Committee on detection, Evaluation,
and treatment of High Blood Pressure. Arch Intern Med. 1993; 153:154-183.
The Sixth Report of the Joint National Committee on Detection, Evaluation,
and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-2446.
Tin LL, Beevers DG and Lip GYH. Systolic vs diastolic blood pressure
and the burden of hypertension. J of Human Hypertens 2002;16:147-150.
UK Prospective Diabetes Study Group. Tight blood pressure control and
risk of macrovascular and microvascular complications in type 2 diabetes:
UKPDS 38. BMJ 1998:317:703-313.
Wilking SV, Belanger AB, Kannel WB, et al. Determinants of isolated
systolic hypertension. JAMA 1988;23:3451-3455.
Williamson J, Chopin JM. Adverse reactions to prescribed drugs in the
elderly: a multicenter investigation. Age and Ageing 1980; 9:73-80.
Wright JT, Agoda L, contreras G, et al. Successful blood pressure control
in the african american study of kidney disease and hypertension. Arch
Intern Med 2002;162:1636-1643. >>Return
A Multicenter, Randomized, Double-Blind, Parallel Group Study
Comparing the Efficacy of a Fixed-Dose Combination of Amlodipine plus
Benazepril HCl Versus Amlodipine in the Treatment of Stage 2 and Stage
Alarming data demonstrate that monotherapy controls little more than
half of all hypertensive patients to current standard goals. Meanwhile,
the sixth report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure (JNC VI) recommend
lower systolic and diastolic levels for all patients, particularly those
with more severe or complicated disease. To help improve blood pressure
control in a greater proportion of the population with Stage 2 and Stage
3 hypertension, this study tests the hypothesis that first-line therapy
with a fixed-dose combination will achieve treatment success in a greater
percentage of patients, as compared to monotherapy. This randomized,
double-blind, placebo controlled study has a primary endpoint achievement
of systolic blood pressure (SPB) > 25 mm HG for patients with baseline
SPB < 180 mm Hg, or > 32 mm HG for patients with baseline SPB
> 180 mm Hg. Secondary objectives include a reduction in diastolic
blood pressure (DBP) ≥ 15 mm Hg for patients with baseline DBP
< 110 mm HG, or ≥ 20 mm Hg for patients with baseline DBP ≥
110 mm Hg. Participants (n=364) received amlodipine/benazepril HCl 5/20
mg or amlodipine 5 mg for two weeks. If target pressure (< 130/85
mm Hg) was not reached by Week 2, patients were titrated to amlodipine/benazepril
HCl 10/20 mg or amlodipine 10 mg, with the possibility of later adding
hydrochlorothiazide (HCTZ) at 12.5 mg if uncontrolled pressure persisted.
At 12 weeks, 74.2% of participants in the combination group (n=182)
achieved first treatment success in systolic blood pressure, compared
to 53% of participants in the monotherapy group (n=178). The difference
of 20.2% was statistically significant (p < .0001). Additionally,
at 12 weeks, 67% of participants in the combination group achieved first
treatment success in diastolic blood pressure, compared to 48.3% of
participants in the monotherapy group. This difference of 18.7% was
also statistically significant (p = .0003). Statistically significant
also was the difference in the percentage of combination-therapy patients
(12.6%) and that of monotherapy patients (23%) experiencing peripheral
edema. We conclude that initial therapy with a fixed-dose may be efficacious
than conventional monotherapy for achieving blood pressure goals in
a greater proportion of Stage 2 and Stage 3 hypertension patients. A
fixed-dose combination approach appears to result in fewer cases of
Hypertension is the most common cardiovascular disease in the United
States, affecting nearly 60 million American adults (AHA, 2003). At
the same time, the persistent rate of uncontrolled hypertension remains
alarming. Monotherapy controls to goal (<140/ 90 mm HG) in only about
50%-60% of all hypertensive patients (Materson, 1993). Further, a high
rate of adverse events, especially ankle edema, has been correlated
with the discontinuation of certain hypertensive single-agent therapies.
Therefore, when monotherapy with first-line antihypertensive agents
is inadequate in reducing blood pressure or is not well tolerated, combination
therapy may be preferential. Recent data indicate that multi-drug therapy
may better equip hypertensive patients to reach goal through multiple,
complementary mechanisms of action (UK Prospective Diabetes Study Group,
besylate/benazepril hydrochloride (HCl) is a fixed combination with
a dihydropyridine (DHP) calcium channel blocker (CCB) and a nonsulfhydryl
angiotensin converting enzyme (ACE) inhibitor. CCB's are potent antihypertensive
agents that act directly on vascular smooth muscle to reduce peripheral
vascular resistance and subsequently to reduce blood pressure. ACE inhibitors
are thought to have benefits beyond their ability to lower blood pressure.
The HOPE trial underscored the role of the renin angiotensin system
(RAS) in cardiovascular disease, since study subjects with documented
coronary artery disease who were given ramipril experienced fewer events
and had lower cardiovascular mortality than placebo patients (HOPE Study
Investigators, 2000). Additionally, the combination of amlodipine and
benazepril has demonstrated improved tolerability, particularly the
added benefit of reducing amlodipine-related edema (Kuschnir, 1996).
of Lotrel and Amlodipine in a Comparative Efficacy Trial (SOLACE) is
designed to study the efficacy and tolerability of amlodipine/benazepril
HCl versus amlodipine in the treatment of Stage 2 and Stage 3 hypertension.
The study's primary objective is to compare the percentage of study
subjects who at 12 weeks have achieved a reduction in systolic blood
pressure (SPB) > 25 mm HG when baseline SPB is < 180 mm Hg, or
a reduction in SPB > 32 mm HG when baseline SPB is > 180 mm Hg.
The secondary objective is to compare the percentage of study subjects
who at 12 weeks have achieved a reduction in diastolic blood pressure
(DBP) ≥ 15 mm Hg when baseline DBP is < 110 mm HG, or a reduction
in DBP ≥ 20 mm Hg when baseline DBP is ≥ 110 mm Hg.
A total of 364 subjects with moderate to severe hypertension were randomized
to one of two dose levels of each treatment according blood pressure.
Moderate to severe hypertension was defined as SBP > 160 mm Hg and
< 210 mm HG with diastolic blood pressure (DBP) > 100 mm Hg and
< 120 mm Hg. Previously treated patients were washed off of all antihypertensive
medications for 72 hours, which was extended by one week if necessary.
Figure 1 illustrates the SOLACE study design.
364 patients enrolled in the study and randomized to one of the two
dose levels, according to blood pressure staging, 62 patients discontinued
study drug. Thus, the intent-to-treat population was 360 patients. The
disposition of these study patients is summarized in Table 1. At Week
0, patients with SPB > 160 mm Hg and < 210 and DPB > 100 mm
HG and < 120 mm Hg at were randomized to Dose Level 1 (amlodipine/benazepril
HCl 5/20 mg or amlodipine 5 mg) for two weeks. At Week 2, patients achieving
a target blood pressure of < 130/85 mm Hg continued treatment at
Dose Level 1, while patients not achieving goal were titrated to Dose
Level 2 (amlodipine/benazepril HCl 10/20 mg or amlodipine 10 mg). Subsequently,
any patient with a blood pressure measurement > 130/85 mm Hg at any
time during the study were also titrated to Dose Level 2. If after Week
3, patients at Dose Level 2 had SBP > 180 and < 210 and/or DBP
> 100 and < 120 mm HG, hydrochlorothiazide (HCTZ) was added at
12.5 mg. Downward dose adjustment to the previous dose level was not
permitted. Patients were discontinued who had SBP > 210 mm Hg and/or
DBP >120 mm HG at any time during the study.
and Exclusion Criteria
Study subjects were men and women between the ages of 18 and 80 years
with a diagnosis of Stage 2 or Stage 3 hypertension. Women of childbearing
potential were required to practice an effective method of contraception.
Pregnant and nursing mothers were excluded. Study subjects were also
excluded from enrollment if they had SBP > 210 mm HG and/or DBP >
120 mm HG. Other exclusion criteria included the following: greater
than 1 gram per day of proteinuria; evidence of hepatic disease; impaired
renal function or renal artery stenosis; history of malignancy; significant
autoimmune disorders; clinically significant arrhythmias, malignant
hypertension; significant history of coronary artery disease within
6 months; cerebrovascular accident, thrombic stroke, or transient ischemic
attack; hypertensive retinopathy; clinically relevant valvular disease;
type 1 or type 2 diabetes mellitus; history of drug or alcohol abuse;
a current prescription of lithium; abnormal physical or laboratory findings;
allergy and/or hypersensitivity to amlodipine, banazepril, angiotensin
converting enzymes, calcium channel blockers, hydrochlorothiazide or
any f their components; prior participation in an investigational clinical
trial within the past 30 days; and beta-blocker use for coronary artery
characteristics of the intent-to-treat population, including ages, sex
and race, are presented in Table 2.
and Safety Measures
The first treatment success in SBP, defined as a reduction in SPB ≥
25 mm Hg (if SPB was < 180 mm Hg at baseline) or a reduction in SBP
≥ 32 (if baseline SPB was ≥ 180 mm HG) during the 12-week
treatment period. The first treatment success in DBP was defined as
a reduction in DBP ≥ 15 mm HG (if baseline DBP was < 110 mm
Hg) or a reduction in DBP ≥ 20 mm HG (if baseline diastolic blood
pressure was ≥ 100 mm Hg). The efficacy analysis was performed
on an intent-to-treat (ITT) population, consisting of all randomized
subjects, using the patient’s last non-missing post-baseline assessment
with the last observation carried forward.
analysis for this report included all subjects who were randomized to
take at least one dose of study medication. Assessment for peripheral
(ankle) edema was performed at the Randomization Visit (Week 0), Weeks
2, 5, 8, and 12. Subject weight was taken prior to measurement of ankle
circumference and edema. Ankle circumference and edema height was measured
after patient was standing for at least 5 minutes. A flexible (cloth)
measuring tape was used to take the circumference of both ankles 1 cm
above the medial malleolus and recorded in millimeters.
95% confidence interval for the difference of proportions between the
two treatment groups was calculated as the standard confidence interval
for difference between binomal proportions with a continuity correction.
A CMH test was used to compare the proportions of the two treatment
groups after adjusting for pooled center.
At baseline, the mean SBP was 167.3 mm/Hg for the amlodipine/benazepril
HCl arm and 167.5 for the amlodipine arm. The total mean DBP was 99.6
mm/Hg (100.0 mm Hg in the amlodipine/benazepril HCl arm and 99.6 mm
Hg in the amlodipine arm). Mean pulse rate was 73.8 beats per minute
(73.0 for the amlodipine/benazepril arm and 74.6 for the amlodipine
arm). Height, weight and body mass index of all study participants were
also taken at baseline and are summarized in Table 3.
According to the primary efficacy variable of this study, amlodipine/benazepril
HCl successfully reduced hypertension in a significantly greater proportion
of patients than did amlodipine. Of the 182 patients randomized to amlodipine/benazepril
HCl, 74.2% achieved first treatment success in systolic blood pressure
at week 12 compared to 53% of the 178 patients randomized to amlodipine,
representing a statistically significant difference of 20.2% (p <
.0001). The individual and cumulative tally of SBP first treatment success
is illustrated in Figure 2.
to the secondary efficacy variable of this study, of the 182 patients
randomized to amlodipine/benazepril HCl, 67% achieved first treatment
success in diastolic blood pressure at week 12, compared to 48.3% of
178 patients randomized to amlodipine, representing a statistically
significant difference of 18.7% (p = .0003). The individual and cumulative
tally of DBP first treatment success is illustrated in Figure 3.
of patients needing to titrate from Dose Level 1 to Dose Level 2 was
nearly identical for both treatment arms. Fewer amlodipine/benazepril
HCl patients (10/182) needed to add HCTZ to achieve treatment goal compared
with amlodipine patients (29/182), but the difference was not statistically
Peripheral edema at week 12 was experienced by a significantly smaller
proportion of patients randomized to the amlodipine/benazepril HCl study
arm, than patients randomized to the amlodipine study arm. Of the 182
amlodipine/benazepril HCl patients, only 12.6% (n=23) compared with
23% of amlodipine patients (n=41) had ankle edema, representing a statistically
significant difference of -10% (p=.0102). The individual and cumulative
tally of peripheral edema is illustrated in Figure 4. When analyzed
excluding significant dosing errors, the percentages adjusted as follows:
11.8% (n=20) for amlodipine/benazepril HCl patients vs. 20.9% (n=34)
for amlodipine patients, for a difference of –9.02% (p=0.0271).
events causing discontinuation were peripheral edema (3 events [1.6%]
for amlodipine/benazepril HCl patients vs. 9 events [4.9%] for amlodipine
patients); aggravated edema; (1 event [0.5%] for amlodipine/benazepril
HCl patients vs. 7 events [3.8%] for amlodipine patients); cough (1
event [0.5%] for amlodipine/benazepril HCl patients). The most common
adverse events observed during the trial were peripheral edema, aggravated
edema, upper respiratory tract infection, cough, and headache, as summarized
in Table 4.
In the SOLACE study, the fixed combination therapy of amlodipine/benazepril
HCl successfully reduced systolic and diastolic pressure to goal in
a significantly greater percentage of patients than did monotherapy.
While the comparative blood pressure results may not be surprising given
the use of two drugs in fixed combination versus monotherapy; it is
important to provide empirical evidence for the theory that additive
anti-hypertensive effects will result from the combination of two separate
mechanisms of action. Further, the Sixth Report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure (JNC VI) advocates lower blood pressure goals for Stage
2 and Stage 3 hypertension (JNC VI, 1997), and recent studies have indicated
the inadequacies of monotherapy. The Veterans Study observing 1,292
men randomized to one of six single-drug therapies in 15 clinics across
the country found that only 59% of treated patients reached the blood-pressure
goal. Because of this and other data finding that single-drug therapy
is generally unsuccessful at reducing blood pressure more than <10
mm of Hg, JNC VI recommends combination therapy first line.
In a more
recent investigation, the SHIELD study found that the fixed-dose combination
of amlodipine/benazepril HCl provides significantly faster blood pressure
control than monotherapy in diabetic patients, a group at significant
risk for cardiovascular disease (Bacris, 2003). While further prolonged
investigation is needed to evaluate the long-term hypertensive effects
of this combination, these early data suggest that amlodipine/benazepril
HCl is preferable for first-line therapy.
been theorized that combination therapy may ultimately reduce the risk
of certain adverse events by utilizing lower doses of each component
drug (Ambrosioni, 2001). Further, the combination of an ACE inhibitor
and a CCB has demonstrated a decreased likelihood of peripheral edema
(Weir, 2001), as has been born out by this investigation. In a comparison
to patients on monotherapy, this study reports that a smaller proportion
of participants who received combination therapy experienced peripheral
edema. Since edema is known to complicate patient compliance (Faemer,
1995), a first-line therapy that retains potency, while limiting this
problematic side effect, would clearly be a welcome addition to current
Stage 2 and Stage 3 hypertensive patients need more rigorous blood pressure
control than they currently have available with today’s monotherapy
options. The combination of amlodipine/benazepril HCl brought more patients
to goal with less peripheral edema than amlodipine. Thus, fixed-dose
combination therapy is an important therapeutic consideration for first-line
treatment of hypertension.
Ambrosioni E. Pharmacoeconomics of hypertension management: the place
of combination therapy. Pharmacoeconomics 2001;19 (4):337-347.
American Heart Association, Heart Disease and Stroke Statistics: Update,
2003. Accessed at http://www.americanheart.org/presenter.jhtml?identifier=3000090
on April 8, 2003.
Bakris GL, Williams M, Dworkin L. Preserving renal function in adults
with hypertension and diabetes: a consensus approach. Am J Kidney Dis.
Bakris GL and Weir, MR on behalf of the SHIELD Trial Investigators.
Achieving goal blood pressure in patients with type 2 diabetes: conventional
versus fixed-dose combination approaches. In press, 2003.
Faemer KC, Jacobs EW, Phillips CR. Long-term patient compliance with
prescribed regimens of calcium channel blockers. Clin Ther. 1995 Mar-Ap;16(2):316-26.
The Heart Outcomes Prevention Evaluation Study Investigators. Effects
of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular
events in high-risk patients. N Engl J Med 2000; 342:145-153.
Joint National Committee on the Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure: The Sixth Report of the Joint National
Committee on the Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure. Arch Internal Med 1997;157:2413-2446.
Kischnir E, Acuna E, Sevilla D, et al. Treatment of patients with essential
hypertension: amlodipine 5 mg/benazepril 20 mg compared with amlodipine
5 mg, benazepril 20 mg, and placebo. Clin Thera 1996;18:1213-1224.
Materson BJ, Reda DJ, Cushman WC et al, for the Department of Veterans
Affairs Cooperative Study Group on Antihypertensive Agents. Single drug
therapy for hypertension in men. A comparison of six antihypertensive
drugs with placebo. N Eng J Med 1993;328:914-921.
UK Prospective Diabetes Study Group: Tight blood pressure control and
risk of macrovascular and microvascular complication in type 2 diabetes:
UKPDS 38. Br Med J 1998;317:703-713.
Weir MR, Rosenberger C, and Fink JC. Pilot study to evaluate a water
displacement technique to compare effects of diuretics and ACE inhibitors
to alleviate lower extremity edema due to dihydropyridine calcium antagonists.
Am J Hypertens 2001;14(9pt1):963-968.
Figure 1. SOLACE Study Design
Legend: Participants were washed off drug for 72 hours. At
randomization, patients were randomized to Dose Level 1 (amlodipine/benazepril
HCl 5/20 mg or amlodipine 5 mg) for two weeks. If goal was not achieved
by the second week, patients were titrated to Dose Level 2 (amlodipine/benazepril
HCl 10/20 mg or amlodipine 10 mg). Any patient with a blood pressure
measurement > 130/85 mm for the remainder of the study was also randomized
to Dose Level 2. If after Week 3, patients at Dose Level 2 had SBP >
180 and < 210 and/or DBP > 100 and < 120 mm HG, hydrochlorothiazide
(HCTZ) was added at 12.5 mg.
1. Study Disposition
Legend: The safety population includes all randomized subjects
who took at least one dose of study drug. The ITT population includes
all randomized subjects who received study drug and at least one post-baseline
efficacy assessment. The completers population includes all ITT subjects
who completed the trial. The denominator of percentages is the total
number of subjects who discontinued the study.
2. Demographic Characteristics
Legend: These demographics represent the study’s ITT
3. Baseline Vital Signs
Legend: These baseline vital signs represent the study’s
2. Systolic Blood Pressure: Subjects Achieving First Treatment Success
Legend: The first treatment success in systolic blood pressure
is defined as a reduction in systolic blood pressure ≥ 25 mm Hg
if baseline was < 180 mm HG or ≥ 32 if baseline was ≥
180 mm Hg.
3. Diastolic Blood Pressure: Subjects Achieving First Treatment Success
Legend: The first treatment success in diastolic blood pressure
is defined as a reduction in diastolic blood pressure ≥ 15 mm
Hg if baseline was < 110 mm Hg or ≥ 29 if baseline was ≥
100 mm Hg.
4. Subjects with Peripheral Edema
Legend: Edema noted in this data reflects only patients who
had edema during a formal assessment. The analysis was performed using
the patient’s last non-missing post-baseline assessment (i.e.,
the last observation carried forward).
4. Most Common Adverse Events
Legend: The analysis was performed using the patient’s
last non-missing post-baseline assessment (i.e., the last observation
(Avoiding Cardiovascular Events Through Combination Therapy in Patients
Living with Systolic Hypertension): Trial Design and Rationale
Kenneth A. Jamerson1; George L. Bakris2; Bjørn Dahløf3;
Bertram Pitt1; Eric Velzaquz4, Michael A Weber5.
of Michigan Medical Center, Ann Arbor, MI
2 Rush Presbyterian/St. Luke's Medical Center, Chicago, IL
3 University of Goteborg, Sweden
4 Duke Universtiy School of Medicine, Durham, NC
5 SUNY Downstate College of Medicine, Brooklyn, NY
Large-scale hypertension studies have demonstrated that most patients
require combination antihypertensive therapy to achieve recommended
target blood pressure goals. ACCOMPLISH (Avoiding Cardiovascular Events
through Combination Therapy in Patients Living with Systolic Hypertension)
is a prospective, randomized, multicenter, double-blind, active-controlled
trial designed to compare the efficacy of initial fixed-dose combination
therapy with amlodipine besylate/benazepril HCl (Lotrel®) with that
of benazepril HCl/Hydrochlorothiazide (HCTZ) on cardiovascular (CV)
morbidity and mortality in high-risk hypertensive subjects. ACCOMPLISH
is the first major hypertension trial of initial therapy with fixed-dose
combination therapy. The study will enroll approximately 12,600 subjects
from the US and Europe. Men and women aged ≥ 60 years old with
systolic blood pressure ≥160 mm Hg and diastolic blood pressure
≤ 115 mm Hg (if previously untreated) will be eligible for the
trial if they have CV disease (prior myocardial infarction [MI] or stroke
or current diabetes) or evidence of impairment in at least two target
organs. In this study, target blood pressure is defined as <140/90
mm Hg. Subjects will be randomized to either amlodipine/benazepril HCl
5/20 mg or benazepril HCl/HCTZ 20/12.5 mg for one month. If target blood
pressure is not achieved, the dosage will be force titrated to amlodipine
besylate/benazepril HCl 5/40 mg or benazepril HCl/HCTZ 40/12.5 mg. If
target blood pressure target is still not reached, the dosage will be
force titrated to amlodipine besylate/benazepril HCl 10/40 mg or benazepril
HCl/HCTZ 40/25 mg. Beta-blockers, alpha-blockers or loop diuretics will
be permitted as add-on therapy as needed if target blood pressure is
not achieved by three months. The primary endpoint is time to first
composite CV event (fatal or nonfatal MI or stroke or hospitalization
for heart failure, unstable, angina, or revascularization). ACCOMPLISH
will begin enrolling in mid-2003 with a completion date planned for
Numerous hypertension trials have demonstrated that patients need combination
antihypertensive therapy in order to achieve recommended target blood
pressure goals of <140/90 mm Hg, or <130/80 mm Hg for patients
with diabetes or chronic kidney disease (UK Prospective Diabetes Study
Group, 1998; Estacio, 1998; Hebert 1997; Hansson, 1998; Wright, 2002;
Lewis, 2001; Cushman, 2002). The ALLHAT trial is a good example of compelling
evidence to support treating hypertension with combination therapy (Cushman,
2002; ALLHAT; 2002). The study included data from 33,357 hypertensive
patients followed for an average of 4.9 years. All participants were
aged ≥ 55 years old and had at least one risk factor for coronary
heart disease (CHD) in addition to hypertension. At least 2 antihypertensive
medications were required in the majority of patients ––
63% –– to achieve blood pressure control (<140/90 mm
Hg). Results from trials finding multiple agents are needed to achieve
target blood pressure are summarized in Figure 1. Moreover, multiple
drug therapy is recommended for the treatment of hypertension in high-risk
populations to achieve target blood pressure goals and reduce the risk
of CV complications (JNC Six, 1997; Douglas, 2003). Taking note of this
trend, the Seventh Report of the Joint National committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure provides
new guidelines for hypertension prevention and management, including
treatment with more than one antihypertensive medication for most patients
logical step in hypertension research is the comparison of fixed-dose
vs fixed-dose combination therapies using different pharmacological
classes. The results of ALLHAT demonstrate the efficacy and safety of
thiazide-type diuretics, calcium channel blockers (CCBs), and angiotensin-converting
enzymes (ACE) inhibitors for reducing CV events in patients with hypertension.
The ACCOMPLISH trial will address the next important question in hypertension
management: namely, what is the optimal antihypertensive combination
regimen to reduce the incidence of CV events?
of an ACE inhibitor and amlodipine has been shown to have synergistic
effects on nitric oxide production (Zhang, 2000), raising the interesting
possibility that specific combinations of antihypertensives may be particularly
beneficial in atherosclerotic plaque stabilization and the prevention
of CV events.
is the first major hypertension trial to compare the efficacy of initial
therapy with fixed-dose combination therapy on CV morbidity and mortality
in high-risk patients. ACCOMPLISH is designed to test the hypothesis
that a combination of a CCB plus an ACE inhibitor (amlodipine besylate/benazepril
HCl [Lotrel®]) will reduce CV morbidity and mortality to a greater
extent than a combination of an ACE inhibitor plus a diuretic (benazepril
Accomplish is a randomized, multicenter, double-blind, parallel group,
active controlled study. The trial is event-driven with an estimated
total treatment duration of approximately 5 years. A total of 12,600
patients will be enrolled into the trial and randomized to one of two
study arms in equal proportions. Following randomization, all subjects
will be treated at Dose Level 1 (amlodipine besylate/benazepril HCl
5/20 mg or benazepril HCl/HCTZ 20/12.5 mg) for 1 month, then force titration
to Dose Level 2 (amlodipine besylate/benazepril HCl 5/40mg or benazepril
HCl/HCTZ 40/12.5 mg for 1 month. Thereafter, if target blood pressure
of < 140/90 mm HG is not achieved, patients
will be titrated to Dose Level 3 (amlodipine besylate/benazepril HCl
10/40 mg or benazepril HCl/HCTZ 40/25 mg).
are encouraged to use a lower target blood pressure (<130/80 mm HG)
in subjects with diabetes or renal disease. If any subject experiences
symptomatic hypotension, they may resume treatment at the previous lower
dose level. After Dose Level 3, subjects may receive add-on antihypertensive
agents based on target blood pressure. Add-on therapies include beta-blockers,
alpha-blockers, clonidine, and loop diuretics.
study design is summarized in Figure 2.
The primary study objective of ACCOMPLISH is to compare the efficacy
of amlodipine besylate/benazepril HCl with that of benazepril HCl/HCTZ
in high-risk hypertensive subjects on the incidence of CV morbidity
and mortality. The secondary study objective is to examine the effects
of the two regimens on the components of the composite primary CVD endpoint
and to evaluate long-term safety and tolerability of each component.
The study population will be comprised of men and women of any racial
background, aged ≥ 60 years old. Patients can be previously treated
or untreated for hypertension. Currently untreated subjects must demonstrate
a mean seated systolic blood pressure of ≥ 160 mm Hg at two consecutive
readings and a mean seated diastolic blood pressure of ≤ 115 mm
Hg. For subjects already taking antihypertensive treatment, the upper
limit of mean seated blood pressure may not exceed 210/115 mm Hg. No
lower limit has been imposed.
subjects already receiving antihypertensive treatment will be withdrawn
from drug and rolled over to one of two arms of randomized trial medication
(either amlodipine besylate/benazepril HCl 5/20 mg or benazepril HCl/HCTZ
20/12.5 mg) without any washout period. Subjects at risk of rebound
after withdrawal of previous medication will be down-titrated during
the screening period prior to being randomized to study drug.
subjects must demonstrate evidence of at least one CV disease or target-organ
damage. The specific list for these inclusion criteria is detailed in
Patients with current angina pectoris and known secondary hypertension
of any etiology will be excluded from ACCOMPLISH. Other exclusion criteria
include the following: refractory hypertension (SBP ≥ 180 mm HG
and/or DBP ≥ 110 mm HG unresponsive to triple-drug regimens of
sympatholytics, diuretics and vasodilators and a history of symptomatic
heart failure (NYHA classes II-IV) or known ejection fraction < 40%.
The primary endpoint will be defined as time to first event of composite
CV morbidity and mortality. For the purposes of ACCOMPLISH, CV morbidity
will be defined as nonfatal, clinically evident acute MI; nonfatal stroke;
hospitalization for unstable angina; and coronary revascularization
procedure (percutaneous coronary intervention [PCI] or coronary artery
bypass graft [CABG]). CV mortality will be defined as death due to sudden
cardiac event, fatal MI, fatal stroke, death due to coronary intervention,
death due to congestive heart failure (CHF) or other CV causes.
The secondary endpoints will be assessed separately as follows: all-cause
mortality; incident diabetes using the ADA definition, progression of
renal disease as defined by a doubling of serum creatinine or progression
to end-stage renal disease.
Other variables to be considered include: hospitalization for CHF requiring
IV diuretics or ionotropes (including emergency room visits; all hospitalizations;
combined coronary disease morbidity, whether fatal or not; acute MI,
hospitalization for unstable angina, and coronary revascularization;
renal function; LVH by ECG; worsening or new onset angina requiring
hospitalization; and peripheral arterial revascularization procedure.
Subgroups of patients will be evaluated as follows: patients with diabetes
at baseline, patients with documented coronary artery disease at baseline,
and patients with chronic renal insufficiency at baseline. Subgroups
will also be evaluated by gender, race and age (<70, ≥ 70 years
ACCOMPLISH is designed to test the hypothesis that benazepril/amlodipine
will reduce cardiovascular morbidity and mortality to a greater extent
than a combination of benazepril/HCTZ. This study will evaluate high-risk
hypertensive patients with documented CAD, coronary equivalents, or
other patients at high risk for cardiovascular events. As ACE inhibitors
have now become the drugs of choice in hypertensive patients with diabetes,
renal insufficiency, and/or proteinuria, the use of the ACE inhibitor
benazepril in both treatment groups allows for the inclusion of these
important high-risk patient subgroups to be studied.
treatment and control of blood pressure have been clearly shown to lower
cardiovascular risk, without any clear lower threshold for blood pressure
reduction. It is important to attempt to achieve goal blood pressure
(<140/90 mm Hg) for the patients in ACCOMPLISH, with lower target
goals defined for patients with diabetes or renal insufficiency.
provides a two-step dose titration method, followed by additional add-on
therapy to achieve goal. Results of previous large clinical trials evaluating
the effects of various monotherapies on morbidity and mortality have
been confounded by the use of frequent add-on therapy, which were necessary
to achieve blood pressure control. It is anticipated that a large proportion
of patients in ACCOMPLISH will be controlled with randomized combination
therapy, without needing further add-on therapy. This should make interpretation
of study results more straightforward. For the high-risk hypertensive
group enrolled in ACCOMPLISH, the annual first event rate is assumed
to be 3.5% for the control group (benazepril/HCTZ). The sample size
is calculated to detect a 15% reduction in the event rate for the amlodipine
besylate/benazepril HCl group with 90% power. In order to fulfill these
assumptions, a total of 1642 events at final analysis are required for
both treatment groups combined. To allow for a rate of 5% for patients,
who permanently discontinue treatment prior to trial end, a total of
12,6000 randomized patients are planned. In this regard, it is crucial
that efforts are made to keep patients in the trial. If a patient does
permanently discontinue study treatment, the patient will be followed
for the duration of the trial.
ACCOMPLISH is the first major hypertension outcome trial to assess two
different fixed-dose combination as initial therapy in patients with
systolic hypertension. Enrollment begins in 2003, with a planned completion
date of 2008.
Chobanian AV, Bakris GL, Black HR et al. The seventh report of the joint
national committee on prevention, detection, evaluation and treatment
of high blood pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.
Cushman WC, Ford CE, Cutler JA et al. Success and predictors of blood
pressure control in diverse North American settings: the Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
J Clin Hypertens. 2002;4:393-405.
Douglas JG, Bakris GL, Epstein M, et al for the Hypertension in African-Americans
Working Group of the International Society on Hypertension in Blacks.
Management of high blood pressure in African Americans consensus statement
of the Hypertension in African Americans Working group of the International
Society on Hypertension in Blacks. Arch Intern Med. 2003;35:195-202.
Estacio RO, Schrier RW. Antihypertensive therapy in type 2 diabetes:
implications of appropriate blood pressure control in Diabetes (ABCD)
trial Am J Cardiol 1998:82:9R-14R.
Hansson L, Zanchetti A, Carruthers SG, et al., for the HOT Study Group.
Effects of intensive blood-pressure lowering and low-dose aspirin in
patients with hypertension: principal results of the Hypertension Optimal
Treatment (HOT) randomized trial. Lancet. 1998;351:1755-1762.
Hebert LA, Kusek JW, Greene T, et al, for the Modification of Diet in
Renal Disease Study Group. Effects of blood pressure control on progressive
renal disease in blacks and whites. Hypertension 1997;30:428-435. Joint
National Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure. The sixth report of the Joint National Committee
on Prevention, Detection, Evaluation, and treatment of High Blood Pressure.
Arch Intern Med, 1997;157:2413-2446.
Lewis EJ, Hunsicker LG, Clarke WR, et al. For the Collaborative Study
Group. Renoprotective effect of the angiotensin-receptor antagonist
irbesartan in patients with nephropathy due to type 2 diabetes. N Engl
J Med. 2001:345:851-860.
The ALLHAT Officers and Coordinators for the ALL HAT Collaborative Research
Group. Major outcomes in high-risk hypertensive patients randomized
to angiotensin-converting enzyme inhibitor or calcium channel blocker
vs diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT). JAMA 2002:288:2981-2997. UK
Prospective Diabetes Study Group. Tight blood pressure control and risk
of macrovascular and microvascular complications in type 2 diabetes:
UKPDS 38. BMJ 1998;217:703-713.
Wright JT Jr., Bakris GL, Green T, et al. Effect of blood pressure lowering
and antihypertensive drug class on progression of hyperten