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Draft Peer-Review Articles
1. Hepatocellular Carcinoma: Overcoming Challenges in Disease Management (read article below)
2. Lercanidipine’s Safety Profile: The Benefits of Lipophilicity (read article below)
3. Shifting the Clinical Paradigm: Treating Systolic Blood Pressure to Goal (read article below)
4. 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 3 Hypertension (The Solace Study Write Up.) (read article below)
5. ACCOMPLISH (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)
1. Article:
Hepatocellular Carcinoma:
Overcoming Challenges in Disease ManagementRobert G. Gish, MD
Division of Hepatology and Complex GI,
Physician’s Foundation at CPMC and
Departments of Medicine and Transplantation,
California Pacific Medical Center, San Francisco, CaliforniaAbbreviations 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.
Address 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: gishr@sutterhealth.org; Fax: (415) 776-0292.
Abstract
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 disease.
Introduction
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.Epidemiology
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.7Much attention 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
Several 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
Other studies 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
Risk Factors
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.As the 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
Pathogenesis 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 damage.18HCC is 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.
Tumor growth 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 structures.3
Clinical 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 Table 3.The life 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.
Diagnosis
[subhead]
Serologic Testing
[copy]
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.Recently, 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.
[subhead]
Imaging
[copy]
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
[subhead]
Biopsy
[copy]
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.Staging
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 cirrhosis.34
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 in use.32Treatment Algorithms
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.36HCC is 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
A more 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
Management 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.
Current Treatment Options
[subhead]
Surgical Intervention: Liver Resection
[copy]
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
[subhead]
Liver Transplantation
[copy]
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.The model 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 survival rate.50
[subhead]
Local Tumor Ablation
[copy]
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
[subhead]
Pharmaceutical/Non-surgical Approaches
[copy]
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.43,54,55Arterial 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
Conclusion
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 alike.On the 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.
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2. Article:
Lercanidipine’s Safety Profile: The Benefits of LipophilicityAbstract
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 blockersIntroduction
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.The addition 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.
Improved 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.
Lercanidipine: 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 side chain.[Insert figure 1. Molecular structure of lercanidipine. Must get permission from Herbette]
Once the 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)
Pharmacokinetic Properties
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)Important 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.
Partition Coefficient
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.[Insert Table 1. Membrane partition coefficients in cardiac model membranes at aring cholesterol to phospholipid (C:L) mole rations Must get permission from Herbette]
Lacipidine
Lercanidipine
Amlodipine
Nitrendipine
Isradipin
NimodipineWashout Kinetics
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.Cholesterol Tolerance
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)Onset of Action
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.Efficacy
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.Further 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. ,
When administered 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).
Thus these 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.
Safety Profile
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.[Insert Table 2. Most commonly reported Adverse Events (Aes) in each treatment group by different system/organ class. Must get permission from Testa et al.]
In general, 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.
Fogari 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 H2O).
Further, 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.
Thus, lercanidipine appears to be a reliably tolerable calcium antagonist with lower incidence of peripheral edema, compared to its less lipophilic counterparts.
Conclusion
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.
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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.
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hypertensives. Am J Hypertens (In press). >>Return to TOP
3. Article:
Shifting the Clinical Paradigm: Treating Systolic Blood Pressure to Goal
Abstract
A 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.Introduction
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 practice.History 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).The trend 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 (Tin, 2002).
Twenty-two 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 pulse pressure.
Clinical 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, 2000).”The evidence 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.
Lack of Awareness
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.Because 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.
Successfully 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.The African 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.
Calcium Channel Blockers
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).While calcium 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.
Conclusion
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.References
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: Philadelphia, 1931.
Guidelines Subcommittee, World Health Organization-International Society of Hypertension Guidelines for the management of hypertension. J Hypertens 1999;17:151-183.
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) S7-S13.
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; 1995:1809-1928.
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.
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Riva-Rocci S. Un Nuovo Sfigmomanometro. Gazzetta Medica di Torino 1896; 50;981-996.
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. JAMA 19999;282:539-546.
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 to TOP
4. Article:
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 3 HypertensionABSTRACT
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 peripheral edema.
INTRODUCTION
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, 1997;Bakris, 2000).Amlodipine 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).
The Study 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.
METHODS
Study Design
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.Of the 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.
Inclusion 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 disease.Demographic characteristics of the intent-to-treat population, including ages, sex and race, are presented in Table 2.
Efficacy 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.The safety 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.
Statistics
The 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.RESULTS
Baseline Data
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.Efficacy
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.According 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.
The proportion 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 significant.
Safety
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).Adverse 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.
DISCUSSION
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.
It has 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 therapeutic options.
Conclusion
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.References
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. 2000;36:646-666.
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.FIGURES & TABLES
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.Table 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.Table 2. Demographic Characteristics
Legend: These demographics represent the study’s ITT populationTable 3. Baseline Vital Signs
Legend: These baseline vital signs represent the study’s ITT population.Figure 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.Figure 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.Figure 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).Table 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 carried forward).
5. Article:
(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 Weber5.1 University 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, NYABSTRACT
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 2008.INTRODUCTION
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 (Chobanian, 2003).The next 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?
The combination 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.
ACCOMPLISH 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 HCl/HCTZ).
STUDY DESIGN
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).Investigators 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.
The complete study design is summarized in Figure 2.
STUDY OBJECTIVES
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.STUDY POPULATION
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.Eligible 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.
All study subjects must demonstrate evidence of at least one CV disease or target-organ damage. The specific list for these inclusion criteria is detailed in Table 1.
Exclusion Criteria
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%.Primary Endpoint
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.Secondary Endpoint
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
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.
Subgroup Analysis
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 old).DISCUSSION
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.Aggressive 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.
The study 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.
CONCLUSION
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.References
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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
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