Document Detail

A current evaluation of the safety of angiotensin receptor blockers and direct renin inhibitors.
Jump to Full Text
MedLine Citation:
PMID:  21633727     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The safety of angiotensin II receptor blockers (ARBs) for the treatment of hypertension and cardiovascular and renal diseases has been well documented in numerous randomized clinical trials involving thousands of patients. However, recent concerns have surfaced about possible links between ARBs and increased risks of myocardial infarction and cancer. Less is known about the safety of the direct renin inhibitor aliskiren, which was approved as an antihypertensive in 2007. This article provides a detailed review of the safety of ARBs and aliskiren, with an emphasis on the risks of cancer and myocardial infarction associated with ARBs. Safety data were identified by searching PubMed and Food and Drug Administration (FDA) Web sites through April 2011. ARBs are generally well tolerated, with no known class-specific adverse events. The possibility of an increased risk of myocardial infarction associated with ARBs was suggested predominantly because the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial reported a statistically significant increase in the incidence of myocardial infarction with valsartan compared with amlodipine. However, no large-scale, randomized clinical trials published after the VALUE study have shown a statistically significant increase in the incidence of myocardial infarction associated with ARBs compared with placebo or non-ARBs. Meta-analyses examining the risk of cancer associated with ARBs have produced conflicting results, most likely due to the inherent limitations of analyzing heterogeneous data and a lack of published cancer data. An ongoing safety investigation by the FDA has not concluded that ARBs increase the risk of cancer. Pooled safety results from clinical trials indicate that aliskiren is well tolerated, with a safety profile similar to that of placebo. ARBs and aliskiren are well tolerated in patients with hypertension and certain cardiovascular and renal conditions; their benefits outweigh possible safety concerns.
Authors:
Helmy M Siragy
Related Documents :
6853907 - Sensitivity of two-dimensional echocardiography in the direct visualization of atrial s...
12467807 - Simultaneous repair of pectus excavatum and congenital heart disease over the past 30 y...
17876387 - Congenital absence of the pericardium presenting as acute myocardial necrosis.
2012427 - Percutaneous transaortic closure of postinfarctional ventricular septal rupture.
6485997 - Thromboxane a2 in acute myocardial infarction.
21172497 - Three-dimensional echocardiography for the preoperative assessment of patients with lef...
Publication Detail:
Type:  Journal Article; Review     Date:  2011-05-19
Journal Detail:
Title:  Vascular health and risk management     Volume:  7     ISSN:  1178-2048     ISO Abbreviation:  Vasc Health Risk Manag     Publication Date:  2011  
Date Detail:
Created Date:  2011-06-02     Completed Date:  2011-09-27     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  101273479     Medline TA:  Vasc Health Risk Manag     Country:  New Zealand    
Other Details:
Languages:  eng     Pagination:  297-313     Citation Subset:  IM    
Affiliation:
Department of Medicine, and Hypertension Center, University of Virginia Health System, Charlottesville, VA 22908, USA. hms7a@virginia.edu
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Amides / adverse effects*,  therapeutic use*
Angiotensin Receptor Antagonists / adverse effects*,  therapeutic use*
Antihypertensive Agents / adverse effects,  therapeutic use
Fumarates / adverse effects*,  therapeutic use*
Humans
Hypertension / drug therapy
Myocardial Infarction / chemically induced
Neoplasms / chemically induced
Chemical
Reg. No./Substance:
0/Amides; 0/Angiotensin Receptor Antagonists; 0/Antihypertensive Agents; 0/Fumarates; 502FWN4Q32/aliskiren
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Vasc Health Risk Manag
Journal ID (publisher-id): Vascular Health and Risk Management
ISSN: 1176-6344
ISSN: 1178-2048
Publisher: Dove Medical Press
Article Information
Download PDF
© 2011 Siragy, publisher and licensee Dove Medical Press Ltd.
License:
Received Day: 17 Month: 5 Year: 2011
collection publication date: Year: 2011
Print publication date: Year: 2011
Electronic publication date: Day: 19 Month: 5 Year: 2011
Volume: 7First Page: 297 Last Page: 313
ID: 3104607
PubMed Id: 21633727
DOI: 10.2147/VHRM.S15541
Publisher Id: vhrm-7-297

A current evaluation of the safety of angiotensin receptor blockers and direct renin inhibitors
Helmy M Siragy
Professor of Medicine and Endocrinology, Department of Medicine, Director, Hypertension Center, University of Virginia Health System, Charlottesville, VA, USA
Correspondence: Correspondence: Helmy M Siragy, University of Virginia, Box 801409, Charlottesville, VA, 22908, USA, Tel +1-434 924 5629, Fax +1 434 982 3626, Email hms7a@virginia.edu

Introduction

The renin-angiotensin system (RAS) consists of a group of hormones, which regulates blood pressure (BP), fluid and electrolyte balance, tissue perfusion, and vascular growth.1,2 The RAS plays an important role in the pathophysiology of cardiovascular and renal disease,3 and antihypertensive therapies that target the RAS are used in the management of hypertension, congestive heart failure, myocardial infarction, stroke, high cardiovascular risk, diabetes, and renal failure.2,3 In addition, antihypertensive drugs that block the RAS may provide organ protection by acting on local RAS functions in tissues, such as the kidneys, heart, eyes, and brain.2,3

Angiotensin-converting enzyme (ACE) inhibitors (eg, ramipril, captopril, enalapril, fosinopril) were the first class of RAS-blocking agents to become available, and ACE inhibitors have been a cornerstone of antihypertensive therapy for many years.4 Numerous clinical trials have shown that the BP-lowering effects of ACE inhibitors provide cardiovascular protection;5 however, ACE inhibitors are associated with treatment-related adverse events (AEs) including persistent dry cough6,7 and angioedema.8 Both of these AEs are more common among black and Asian patients compared with white patients,5,8 and cough is also more common among women and nonsmokers.7 Cough is typically managed by discontinuing ACE inhibitor therapy or by decreasing the dose. Antitussives and antihistamines are usually ineffective for managing cough; however, in some cases cough may disappear spontaneously.6 Strategies for managing angioedema include discontinuation of ACE inhibitor therapy and/or treatment with antihistamines or epinephrine.8 Further, although several case reports have suggested a relationship between the use of ACE inhibitors and development of cancer, case-control and longitudinal studies have shown no relationship and, in some cases, a protective effect from treatment.9,10

Over the last two decades, several angiotensin II receptor blockers (ARBs; eg, losartan, valsartan, telmisartan, olmesartan) have been approved as antihypertensive therapies.11 ARBs provide clinically meaningful benefits for patients with cardiovascular and/or renal disease,11 and ARBs generally have better tolerability profiles than ACE inhibitors.12 Cough is not an AE associated with ARB therapy; however, when ARBs are used in combination with ACE inhibitors, there is an increased risk of renal dysfunction and hyperkalemia.4 Over the past several years, concerns have surfaced about possible links between ARBs and increased risks of cancer13 and myocardial infarction.14

Direct renin inhibitors (DRIs) are a new class of anti-hypertensive agents that target the initial rate-limiting step of the RAS.15 Several DRIs have been developed as antihypertensive therapies; however, early DRIs, including enalakiren, remikiren, and zankiren, had poor bioavailability, weak antihypertensive effects, and short durations of action.4,15 Aliskiren is the only DRI that is approved by the United States Food and Drug Administration (FDA) for the treatment of hypertension,16 but several other DRIs are in the early stages of clinical development.17,18 In clinical studies, the AE profile of aliskiren was similar to that of placebo, with a lower incidence of cough than ACE inhibitors.15,16

The main purpose of this article is to review the safety of ARBs and the DRI aliskiren, including a detailed examination of the risks of cancer and myocardial infarction associated with ARBs. A brief overview of the RAS and efficacy of ARBs and aliskiren is also provided.


Overview of the RAS

Key steps in the RAS are shown in Figure 1.3 Following conversion from its precursor prorenin, the aspartate protease renin is secreted by granular cells of the juxtaglomerular apparatus in the kidney.3,19 The biosynthesis and release of renin are key elements in determining the capacity of the RAS to regulate BP and respond to fluid changes.3 Renin catalyzes the conversion of angiotensinogen to angiotensin I, which is the rate-limiting step in the RAS.15 DRIs block this step and reduce plasma renin activity.15 ACE catalyzes the conversion of angiotensin I to angiotensin II, and ACE inhibitors block this step in the RAS.15 Angiotensin II binds to angiotensin II type-1 (AT1) receptors, which regulates BP via several mechanisms and provides feedback inhibition of further release of renin by the kidneys.15 ARBs block the AT1 receptor, reducing the effects of angiotensin II.4

ARBs and ACE inhibitors may not provide comprehensive suppression of the RAS because they disrupt the negative feedback effect of angiotensin II on renin release, resulting in an increase in plasma renin concentration and plasma renin activity.2,4 ACE inhibitors also increase angiotensin I concentrations, and although ACE inhibitors prevent the conversion of angiotensin I to angiotensin II, angiotensin II production can still occur through non-ACE–dependent pathways involving enzymes such as chymase and chymotrypsin-like angiotensin-generating enzyme.1,15 In addition, ACE inhibitors block the degradation of bradykinin, and the resulting increase in bradykinin concentration may be a factor in the development of cough and angioedema associated with these agents.15 DRIs may provide more optimal suppression of the RAS by interrupting the system at its first regulated step, resulting in decreased plasma renin activity.1,2,15


Efficacy of ARBs and the DRI aliskiren

In 1995, losartan was the first ARB to receive FDA approval as an antihypertensive. Since then, six other ARBs and the DRI aliskiren have also been approved for the treatment of hypertension; several of these agents also have other cardiovascular indications.20 Approved indications, dosing information, and dates of FDA approval for the ARBs and aliskiren are shown in Table 1.

ARBs

Data from numerous randomized clinical trials indicate that ARB therapy is effective in reducing complications related to hypertension5 and in slowing or blocking the progression of cardiovascular disease.11 As a class of drugs, ARBs have shown clinical benefits for patients with heart failure, diabetes, and chronic kidney disease.5 Pharmacologic and dosing differences exist among the seven ARBs approved as antihypertensive agents;11,20 therefore, efficacy and safety results for one ARB cannot be extrapolated to other ARBs.20 In general, newer ARBs are more effective than losartan in lowering BP in patients with hypertension based on the results of head-to-head comparative studies.11 Recent reviews11,20 have compared the efficacy of ARBs vs non-ARBs in different clinical settings. These results are summarized in Table 2.

The DRI aliskiren

The effects of aliskiren on cardiovascular and renal morbidity and mortality are currently unknown. However, several outcomes studies are underway as part of the ASPIRE HIGHER clinical trials program, which will help to better define the role of direct renin inhibition in clinical practice.1

When administered alone or in combination with other agents, including thiazide diuretics, calcium-channel blockers, or RAS-blocking drugs (ie, ACE inhibitors or ARBs), treatment with aliskiren effectively lowers BP in a variety of hypertensive populations (eg, diabetic, obese, elderly).1,21 In several randomized, double-blind clinical trials, treatment with aliskiren has been associated with positive effects on surrogate markers of cardiovascular and renal disease, including urinary albumin, N-terminal pro-brain natriuretic peptide (NT-proBNP), and left ventricular mass index.2224 For example, in the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial in patients with hypertension and type 2 diabetes with nephropathy,22 aliskiren 300 mg/day combined with losartan 100 mg/day reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval [CI]: 9% to 30%; P < 0.001) compared with losartan 100 mg/day plus placebo. In the Aliskiren Observation of Heart Failure Treatment (ALOFT) trial23 involving patients with New York Heart Association (NYHA) class II to IV heart failure and a history of hypertension, addition of aliskiren to an ACE inhibitor (or ARB) and β-blocker significantly reduced NT-proBNP concentrations compared with placebo. In the Aliskiren in Left Ventricular Hypertrophy (ALLAY) trial,24 which included overweight patients with hypertension and increased ventricular wall thickness, treatment with aliskiren or losartan resulted in similar reductions in left ventricular mass index.

In a recent study (Aliskiren Study in Post-MI Patients to Reduce Remodeling [ASPIRE]), adding aliskiren to standard therapy (ie, statins, beta-blockers, antiplatelets, and either ACE inhibitors [given to 90% of the patients] or ARBs [10% of the patients]) in the weeks following an acute myocardial infarction gave no further protection against ventricular remodeling.25 However, the researchers conducted a post-hoc subgroup analysis and found that patients with diabetes (n = 148) were the only subgroup that had a borderline interaction in treatment effect. There were more AEs in patients assigned to aliskiren, but the total number of serious AEs was similar in the two arms. Specifically, AEs that occurred at a higher incidence in aliskiren recipients compared with placebo recipients included hyperkalemia (5.2% vs 1.3%), hypotension (8.8% vs 4.5%), and renal dysfunction (2.4% vs 0.8%). Elevations in blood urea nitrogen and creatinine were more likely in the aliskiren group, and patients assigned to aliskiren were more likely to have a potassium value measured at >5.5 mmol/L or at ≥6 mmol/L. Although these results do not provide support for testing the use of aliskiren in a morbidity and mortality trial in this population of high-risk postmyocardial infarction patients, ASPIRE used a surrogate endpoint and was not powered to assess hard clinical outcomes. Aliskiren is currently being studied in ongoing outcomes trials of patients with chronic heart failure and diabetic nephropathy to assess the role of direct renin inhibition in these populations.


Safety of ARBs and the DRI aliskiren
Safety of ARBs

As a class of agents, ARBs are well tolerated, with safety profiles similar to that of placebo. No class-specific AEs have been associated with ARBs.26 ARBs are contraindicated for women who are pregnant or may become pregnant because of the risk of fetal developmental abnormalities, and ARBs are not recommended for women who are breastfeeding.5 Several antihypertensive drugs have been associated with an increased risk of erectile dysfunction (ED); however, ARBs have not been observed to increase the risk of ED.5 In patients whose renal function may depend on the activity of the RAS (eg, patients with severe congestive heart failure), treatment with ARBs may be associated with oliguria and/or progressive azotemia; rarely, acute renal failure and/or death have been reported in these patients. ARBs may also increase serum creatinine and/or blood urea nitrogen levels in patients with unilateral or bilateral renal-artery stenosis.27,28

ARBs and myocardial infarction

In 2004, an editorial by Verma and Strauss14 raised concerns that ARBs may increase the risk of myocardial infarction based on results of the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial,29 which reported a statistically significant 19% relative increase in myocardial infarction with valsartan compared with the calcium-channel blocker amlodipine. Responses to this article from the medical community were mixed. Several follow-up editorials and analyses3033 cited the need to evaluate the risk of myocardial infarction associated with ARBs more systematically and in a broader clinical context. However, other publications noted that there are possible mechanisms by which ARBs could predispose patients to myocardial infarction.12,34

In 2006, Strauss and Hall12 used the term “ARB-MI Paradox” to describe the unexpected observation that in some clinical trials involving patients at high cardiovascular risk, the BP-lowering effects of ARBs did not reduce the risk of myocardial infarction compared with placebo, and in some cases treatment with ARBs may have increased the risk of myocardial infarction. The authors went on to provide a plausible biological mechanism by which ARBs could increase the incidence of myocardial infarction by increasing circulating levels of angiotensin II. Increased angiotensin II levels cause up-regulation of angiotensin type-2 (AT2) receptors. While AT2-receptor stimulation may provide beneficial effects by mediating vasodilation and nitric oxide release, AT2-receptor stimulation may also mediate growth promotion, fibrosis, and hypertrophy, and may have pro-atherogenic and pro-inflammatory effects. The authors concluded that results from meta-analyses3538 support the “ARB-MI Paradox” because they show that ARBs are associated with an increased risk of coronary heart disease events and/or a lack of BP-related vascular benefits.

Following the publication of the editorial by Verma and Strauss,14 several meta-analyses were performed analyzing cardiovascular event outcomes across multiple clinical trials involving ARBs. Results of these analyses were mixed, with some studies reporting no increased risk of myocardial infarction associated with ARBs,33,35,36 while other studies12,39 report a trend toward increased risk of myocardial infarction with ARBs. While meta-analyses can be powerful tools to summarize data across multiple studies, they also have significant limitations.40 Identification and selection of studies can be biased and availability of results may limit the analyses that can be performed. The choice of statistical analysis methods (ie, fixed-effects vs random-effects models) can also affect the outcome of the meta-analysis. In addition, heterogeneity of data between different studies (eg, disease states, follow-up time, treatment regimens) may make it difficult to create a meaningful integration of results.40 Limitations specifically acknowledged in the meta-analyses that evaluated the risk of myocardial infarction associated with ARBs included heterogeneity of data across studies, limited availability of data on the incidence of myocardial infarction, varying definitions of myocardial infarction between studies, and the potential for confounding effects of different treatments on the incidence of myocardial infarction.35,36

Table 3 shows the incidence of myocardial infarction reported in randomized clinical trials of ARBs that had a mean or median follow-up time of at least 1 year and enrolled at least 1000 patients with a range of cardiovascular and renal conditions. Since the publication of the Verma and Strauss editorial,14 considerably more data have become available on the incidence of myocardial infarction in patients treated with ARBs. Eight landmark, randomized clinical trials involving ARBs have been completed since 2004. None of these trials has shown a statistically significant increase in the incidence of myocardial infarction associated with ARBs compared with placebo or non-ARB active comparators; however, one study (Efficacy of Candesartan on Outcome in Saitama Trial [E-COST])41 in Japanese patients with essential hypertension reported a statistically significant decrease in the risk of myocardial infarction associated with candesartan compared with conventional therapy (relative risk [RR]: 0.44; 95% CI: 0.21–0.84; P < 0.05).

In the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) study,42 which enrolled patients with vascular disease or high-risk diabetes, the RR for fatal or nonfatal myocardial infarction was 1.07 (95% CI: 0.94–1.22) for telmisartan compared with the ACE inhibitor ramipril. The RR for myocardial infarction for combination therapy with telmisartan and ramipril vs ramipril alone was 1.08 (95% CI: 0.94–1.23).42 In the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) study,43 which also included patients with diabetes with end-organ damage, the incidence of myocardial infarction was 3.9% (116/2954) in patients treated with telmisartan and 5.0% (147/2972) in patients who received placebo (hazard ratio [HR] for telmisartan vs placebo, 0.79; 95% CI: 0.62–1.01; P = 0.059).43 Results of the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study44 showed that the event rate for fatal or nonfatal myocardial infarction was not significantly different for valsartan compared with placebo in patients with impaired glucose tolerance and cardiovascular disease or cardiovascular risk factors (HR: 0.97; 95% CI: 0.77–1.23; 1-sided P = 0.41; 2-sided P = 0.83). In the KYOTO HEART study,45 in Japanese patients with uncontrolled hypertension, the HR for acute myocardial infarction for valsartan compared with non-ARB antihypertensive treatment was 0.65 (95% CI: 0.2–1.8; P = 0.39). Results from the Jikei Heart Study46 in Japanese patients with hypertension, coronary heart disease, and/or heart failure showed a HR for new or recurrent acute myocardial infarction of 0.90 (95% CI: 0.47–1.74; P = 0.75) for valsartan compared with non-ARB therapy.

The Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE)47 and Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS)48 studies did not report statistical analyses for the difference in the incidence of myocardial infarction between ARBs (irbesartan and telmisartan, respectively) and placebo; however, the incidences of myocardial infarction were numerically similar between the ARBs and placebo (Table 3), and no significant differences were observed in the HR for death from cardiovascular causes. In the I-PRESERVE study,47 the HR for death from a cardiovascular cause or nonfatal myocardial infarction or stroke was 0.99 (95% CI: 0.86–1.13; P = 0.84) for irbesartan vs placebo, and in the PROFESS study,48 the HR for death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure was 0.94 (95% CI: 0.87–1.01; P = 0.11) for telmisartan vs placebo.

Two other landmark randomized clinical trials involving ARBs are not listed in Table 3 because the published results of these studies did not report the incidence of myocardial infarction. The Valsartan Heart Failure Trial (Val-HeFT) study49 evaluated the effects of valsartan as add-on therapy to standard treatment for heart failure in patients with NYHA class II, III, or IV heart failure. In this study, treatment with valsartan reduced the incidence of mortality and morbidity (defined as cardiac arrest with resuscitation, hospitalization for heart failure, or receipt of intravenous inotropic or vasodilator therapy for ≥4 hours) by 13.2% compared with placebo (RR: 0.87; 97.5% CI: 0.77–0.97; P = 0.009). Results of the Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES) trial50 showed that the incidence density ratio for cardiovascular events (including myocardial infarction and new cardiac failure) over a mean follow-up time of 2.5 years was lower for eprosartan compared with the calcium-channel blocker nitrendipine (0.75; 95% CI: 0.55–1.02; P = 0.06) in patients with hypertension and history of stroke.

ARBs and cancer

A possible link between an increased incidence of cancer and the use of antihypertensive drugs, including β-blockers, calcium-channel blockers, diuretics, and the alkaloid reserpine, has been suggested by several studies.9 However, the majority of these possible associations remain unproven or highly uncertain.9

Results from animal studies have suggested a possible biological mechanism by which ARBs could increase tumor cell proliferation and angiogenesis through selective blockade of AT1 receptors.51 This selective blockade results in increased stimulation of AT2 receptors by angiotensin II. Studies in mice52,53 have shown that AT2-receptor blockade and gene deletion is associated with decreased expression of pro-angiogenic vascular endothelial growth factor and increased expression of thrombospondin-1.

A recent meta-analysis by Sipahi and colleagues13 found a modestly increased risk of cancer associated with ARBs. Based on an analysis of 5 randomized controlled trials that had a follow-up of at least 1 year, the risk of developing new cancer was 7.2% (2510/35015) among patients treated with ARBs, compared with 6.0% (1602/26575) for controls (RR: 1.08; 95% CI: 1.01–1.15; P = 0.016). In the trials included in this analysis, telmisartan was the study drug for 85.7% (n = 30014) of patients who received an ARB. Analysis of the trials involving telmisartan showed that the RR for development of new cancer in patients treated with telmisartan compared with controls was 1.07 (95% CI: 1.00–1.14; P = 0.05).

The authors13 also analyzed the results of 5 trials (N = 68 402) for the occurrence of common types of solid organ cancers (ie, breast, lung, and prostate cancer); these results are summarized in Table 4. New lung cancer occurred more frequently in patients treated with ARBs (0.9% [361/38 422]) than in control groups (0.7% [195/29 980]; RR: 1.25; 95% CI: 1.05–1.49; P = 0.01); no significant differences were observed for prostate or breast cancers. Based on the results of 8 trials that reported cancer deaths, no significant difference was observed between ARBs and controls in the incidence of cancer deaths (1.8% [n = 959/53 424] for ARBs vs 1.6% [n = 639/40 091] for controls; RR: 1.07; 95% CI: 0.97–1.18; P = 0.183).

In addition to the limitations of meta-analyses discussed previously,40 there are several limitations specific to the meta-analysis performed by Sipahi and colleagues13 that should be considered when interpreting these results. The duration of follow-up in the trials included in this meta-analysis ranged from 1.9–4.8 years. Because cancer is a relatively rare occurrence in any time period of less than 5 years, it has been argued that the duration of follow-up in these trials was too short to draw any meaningful conclusions about the development of new cancers.54 In addition, development of cancer is a relatively rare AE, and rare AEs are often not analyzed statistically in randomized clinical trials because of small sample sizes; this problem can persist even when data are pooled.40 It is also important to note that these results are based on post-hoc analyses, and the primary studies were not designed to test for the development of cancer.13 Further, it is not appropriate to draw conclusions about a possible class effect for all ARBs based on results of this meta-analysis because telmisartan was the study drug in 85.7% of patients who received ARBs. Because the different ARBs have unique pharmacologic and dosing properties,20 results heavily weighted for telmisartan cannot be extrapolated to the entire class of medications. As noted by Sipahi and colleagues, publication bias was also a significant limiting factor in this meta-analysis. There is a lack of published and/or publicly available information on the incidence of cancer observed in clinical trials of ARBs.20 Specifically, many large trials (eg, VALUE,29 Study on Cognition and Prognosis in the Elderly [SCOPE]55) did not collect cancer data or did not provide their cancer data to the authors of this study; of 60 trials identified as meeting the inclusion criteria for this analysis, data on cancer incidence and/or cancer deaths were only available from nine trials.13 In addition, the authors of this meta-analysis did not have access to patient-level data to determine whether factors such as age, sex, and smoking status may have influenced the results.13

Subsequently, a second meta-analysis56 was performed to assess whether there is an increased risk of cancer associated with antihypertensive therapy. Results of this analysis56 refuted the results of the Sipahi study.13 In their meta-analysis, Bangalore and colleagues identified 70 randomized clinical trials of antihypertensive agents (ARBs, ACE inhibitors, calcium-channel blockers, and diuretics) involving 324,168 patients and found no increased risk of cancer associated with ARBs compared with placebo or other antihypertensive controls using random-effects and fixed-effect models (Table 5).56 However, in a fixed-effect model, the combination of ARBs with ACE inhibitors was associated with an increased cancer risk compared with placebo and compared with ARBs (Table 5). When the results of individual trials of ARBs were evaluated for cancer risk and cancer-related death, ARBs did not differ significantly vs comparators (Figure 2). In addition, results did not differ for telmisartan compared with other ARBs.

A third meta-analysis,57 conducted by the ARB Trialists Collaboration, evaluated the incidence of cancer in 15 long-term, randomized, controlled trials that involved 138,769 patients at high risk for cardiovascular disease who received ARBs (telmisartan, irbesartan, valsartan, candesartan, or losartan). In this analysis, the trials included were required to have an average follow-up time of at least 12 months. Similar to the Bangalore meta-analysis,56 no increased risk of cancer with ARBs was identified; the cancer incidence in the 15 trials was 6.16% (4549/73,808) in the ARB groups vs 6.31% (3856/61 106) in the control groups (odds ratio [OR]: 1.00; 95% CI: 0.95–1.04; P = 0.886). In addition, no increased cancer risk was observed when evaluating the individual ARBs, and no differences were observed in the incidences of lung, prostate, or breast cancers between ARBs and controls. This analysis also examined cancer risk of ARB/ACE inhibitor combinations vs ACE inhibitors alone, ARBs alone vs ACE inhibitors alone, and ARBs vs placebo/controls without ACE inhibitors. No increased risk of cancer was observed in any of these overall comparisons (Figure 3). A nominal increase in cancer risk was observed with the ARB/ACE inhibitor combination in one trial (ONTARGET) but a reduced cancer risk was observed with this combination in another (VALIANT). Thus, the authors concluded that the increased risk of cancer observed with the ARB/ACE inhibitor combination may be due to chance and that further study is needed to resolve this question.

Because cancer was not a prespecified outcome in most randomized clinical trials involving ARBs, the amount of published information discussing cancer rates in individual randomized clinical trial results is limited. The authors of both the Sipahi13 and Bangalore56 studies searched FDA dockets for information on cancer submitted to the FDA during drug approval processes, labeling changes, and FDA meeting minutes. The authors of the Bangalore study56 also contacted authors and study investigators via email to obtain additional unpublished cancer data. The authors of the ARB Trialists analysis57 had access to individual data for several studies with prespecified methods for cancer identification and tabulated cancer outcomes data for the other trials.

The Bangalore56 and ARB Trialists57 meta-analyses were more robust than the Sipahi meta-analysis13 because more trials were included and multiple comparison analysis was performed on the network of different treatments. However, the authors of the Bangalore study56 acknowledge several limitations including the possibility that the survival benefit associated with antihypertensive therapy compared with placebo may have introduced a “survival bias” that increased the incidence of cancer in active treatment groups. For all the meta-analyses, there may have been other confounding variables that are nearly impossible to measure, such as exposure to radiation or carcinogens. None took into consideration the incidence of a specific cancer in the general population. In addition, the selection criteria used to include trials in these meta-analyses could have influenced the findings (ie, certain trials when put together could increase, decrease, or have no effect on cancer risk). Moreover, results are limited by the short-term nature of most trials and the relatively short duration of exposure to the drugs in question to determine cancer risk. Finally, publication bias, issues with heterogeneity, and availability of data can affect any meta-analysis.

Several population-based studies have evaluated the association between antihypertensive treatment and cancer over the years. A recent analysis by Huang and colleagues specifically investigated the association between ARBs and the occurrence of new cancers in 109,002 patients with newly diagnosed hypertension.58 Patients were identified from a random sample of 1 million individuals of mostly Chinese ethnicity using the Taiwanese National Health Insurance database. Over an average follow-up period of 5.7 years, a total of 9067 cases of new cancer were reported with a signif icantly lower occurrence among patients receiving ARBs than not receiving ARBs (3082 vs 5985; P < 0.001). This was the case after adjusting for age, sex, comorbidities, and medications for hypertension control (HR: 0.66; 95% CI: 0.63–0.68; P < 0.001). Consistent results were observed regardless of ARB and for all types of cancer, although conclusions regarding cause and effect cannot be established.

Based on the results of the Sipahi study, the FDA initiated a safety review of ARBs.59 In July 2010, the FDA issued a communication stating that their results to date indicated that the benefits of ARB therapy outweighed the risks. The FDA did not conclude that ARBs increase the risk of cancer but they will continue their analysis and update the public as more data become available.

Safety of aliskiren

The clinical studies conducted to date with aliskiren have shown this agent to be well tolerated with an AE profile similar to that of placebo, although the treatment duration has been too short to evaluate potential risk for myocardial infarction or cancer. The most commonly reported AEs were fatigue, headache, dizziness, diarrhea, nasopharyngitis, and back pain.15 Because aliskiren does not inhibit or induce cytochrome P450 isoenzymes, it has relatively few interactions with other drugs.15 Aliskiren is contraindicated for women who are pregnant or may become pregnant because of the risk of fetal and neonatal morbidity and mortality associated with drugs that act on the RAS.60

To evaluate the safety and tolerability of aliskiren, White and colleagues pooled safety data from 12 randomized clinical trials of aliskiren involving 12,188 patients with hypertension.16 The studies included in this analysis were categorized as short term (8 weeks) placebo controlled or long term (26–52 weeks) active controlled. In the short-term studies (n = 8862), AEs were reported by 33.6%, 31.6%, and 36.8% of patients treated with aliskiren 150 mg, aliskiren 300 mg, and placebo, respectively. Serious AEs occurred in 0.4%, 0.5%, and 0.7% of patients treated with aliskiren 150 mg, aliskiren 300 mg, and placebo, respectively. The rate of discontinuation due to AEs was ≤ 1.4% for both aliskiren doses and 2.6% for placebo. In the long-term studies (n = 3326), AEs were reported by 33.7% of patients treated with aliskiren 150 mg, 43.2% of patients treated with aliskiren 300 mg, 60.1% of patients treated with ACE inhibitors, 53.9% of patients treated with ARBs, and 48.9% of patients treated with thiazide diuretics. Serious AEs occurred in 3.4% of patients treated with aliskiren (both doses), compared with 2.4%, 8.4%, and 1.7% of patients treated with ACE inhibitors, ARBs, and thiazide diuretics, respectively. The rate of discontinuation due to AEs was 3.2%, 1.7%, 6.9%, 6.5%, and 3.3% for the aliskiren 150-mg, aliskiren 300-mg, ACE inhibitors, ARBs, and thiazide diuretics groups, respectively. Incidences of AEs of special interest (possibly related to RAS agents) are listed in Table 6. The incidence of cough was low for all aliskiren treatment groups; it was similar to that of placebo in the short-term studies and lower than ACE inhibitors in the long-term studies. In the short-term studies, the incidence of abnormalities in prespecified laboratory values was low and similar to placebo. In the aliskiren 150-mg, aliskiren 300-mg, and placebo groups, respectively, 0.9%, 1.6%, and 1.3% of patients had serum potassium levels >5.5 mEq/L at any visit during the double-blind treatment period. In the long-term studies, 5.7% of patients treated with aliskiren 300 mg had serum potassium levels >5.5 mEq/L, compared with 1.9% to 3.7% of patients in all other treatment groups. Overall, the safety profile of aliskiren was similar to that of placebo and similar or superior to other antihypertensive agents.16


Conclusions

ARBs are well tolerated, with a class safety profile similar to that of placebo and no known class-specific AEs. Results from meta-analyses evaluating the risks of myocardial infarction or cancer associated with ARBs have been inconsistent, and caution should be used when evaluating the results of these analyses because even the most well designed and carefully executed meta-analyses have significant limitations. Evidence from landmark, randomized clinical trials published to date does not suggest a link between ARBs and an increased risk of cancer or myocardial infarction. The FDA’s position on ARB use is that the benefits of these drugs outweigh their risks, and the FDA has not concluded that ARBs increase the risk of cancer. The DRI aliskiren is also a well-tolerated antihypertensive drug, with a safety profile that is similar to that of placebo and similar or superior to those of other antihypertensive drugs. As part of the aliskiren ASPIRE HIGHER clinical trials program, studies are ongoing in patients with known cardiovascular or renal risk factors and results of these trials will provide additional data on the overall tolerability profile of aliskiren.1


Notes

Disclosure

The author declares no conflicts of interest.

Technical assistance with editing, figure preparation and styling of the manuscript for submission was provided by Cherie Koch, PhD, and Michael S. McNamara, MS, of Oxford PharmaGenesis Inc., and was funded by Novartis Pharmaceuticals Corporation. The author was fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of this manuscript. The opinions expressed in the manuscript are those of the author and Novartis Pharmaceuticals Corporation had no influence on the contents.


References
1.. Fogari R,Zoppi A. New class of agents for treatment of hypertension: focus on direct renin inhibitionVasc Health Risk ManagYear: 2010686988220957132
2.. Sever PS,Gradman AH,Azizi M. Managing cardiovascular and renal risk: the potential of direct renin inhibitionJ Renin Angiotensin Aldosterone SystYear: 2009102657619502253
3.. Volpe M,Savoia C,De Paolis P,Ostrowska B,Tarasi D,Rubattu S. The renin-angiotensin system as a risk factor and therapeutic target for cardiovascular and renal diseaseJ Am Soc NephrolYear: 200213Suppl 3S173S17812466309
4.. Gullapalli N,Bloch MJ,Basile J. Renin-angiotensin-aldosterone system blockade in high-risk hypertensive patients: current approaches and future trendsTher Adv Cardiovasc DisYear: 20104635937320965951
5.. Chobanian AV,Bakris GL,Black HR,et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood PressureHypertensionYear: 20034261206125214656957
6.. Karlberg BE. Cough and inhibition of the renin-angiotensin systemJ HypertensYear: 199311Suppl 3S49S52
7.. Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice guidelinesChestYear: 20061291 Suppl169S173S16428706
8.. Sica DA,Black HR. Angioedema in heart failure: occurrence with ACE inhibitors and safety of angiotensin receptor blocker therapyCongest Heart FailYear: 20028633434134512461324
9.. Grossman E,Messerli FH,Goldbourt U. Antihypertensive therapy and the risk of malignanciesEur Heart JYear: 200122151343135211465967
10.. Friis S,Sorensen HT,Mellemkjaer L,et al. Angiotensin-converting enzyme inhibitors and the risk of cancer: a population-based cohort study in DenmarkCancerYear: 20019292462247011745304
11.. Verdecchia P,Angeli F,Repaci S,Mazzotta G,Gentile G,Reboldi G. Comparative assessment of angiotensin receptor blockers in different clinical settingsVasc Health Risk ManagYear: 2009593994819997575
12.. Strauss MH,Hall AS. Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradoxCirculationYear: 2006114883885416923768
13.. Sipahi I,Debanne SM,Rowland DY,Simon DI,Fang JC. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trialsLancet OncolYear: 201011762763620542468
14.. Verma S,Strauss M. Angiotensin receptor blockers and myocardial infarctionBMJYear: 200432974771248124915564232
15.. Sanoski CA. Aliskiren: an oral direct renin inhibitor for the treatment of hypertensionPharmacotherapyYear: 200929219321219170589
16.. White WB,Bresalier R,Kaplan AP,et al. Safety and tolerability of the direct renin inhibitor aliskiren: a pooled analysis of clinical experience in more than 12,000 patients with hypertensionJ Clin Hypertens (Greenwich)Year: 2010121076577521029339
17.. Bezencon O,Bur D,Weller T,et al. Design and preparation of potent, nonpeptidic, bioavailable renin inhibitorsJ Med ChemYear: 200952123689370219358611
18.. Tice CM,Xu Z,Yuan J,et al. Design and optimization of renin inhibitors: Orally bioavailable alkyl aminesBioorg Med Chem LettYear: 200919133541354519457666
19.. Fyhrquist F,Saijonmaa O. Renin-angiotensin system revisitedJ Intern MedYear: 2008264322423618793332
20.. Siragy HM. Comparing angiotensin II receptor blockers on benefits beyond blood pressureAdv TherYear: 201027525728420524096
21.. Zheng Z,Shi H,Jia J,Li D,Lin S. A systematic review and meta-analysis of aliskiren and angiotension receptor blockers in the management of essential hypertensionJ Renin Angiotensin Aldosterone SystYear: 2010Month: 11 Day: 8 [Epub ahead of print]..
22.. Parving HH,Persson F,Lewis JB,Lewis EJ,Hollenberg NK. Aliskiren combined with losartan in type 2 diabetes and nephropathyN Engl J MedYear: 2008358232433244618525041
23.. McMurray JJ,Pitt B,Latini R,et al. Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failureCirc Heart FailYear: 20081172419808266
24.. Solomon SD,Appelbaum E,Manning WJ,et al. Effect of the direct renin inhibitor aliskiren, the angiotensin receptor blocker losartan, or both, on left ventricular mass in patients with hypertension and left ventricular hypertrophyCirculationYear: 2009119453053719153265
25.. Solomon SD,Hee SS,Shah A,et al. Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunctionEur Heart JYear: 2011 [Epub ahead of print]..
26.. Mazzolai L,Burnier M. Comparative safety and tolerability of angiotensin II receptor antagonistsDrug SafYear: 1999211233310433351
27.. Cozaar® (losartan potassium tablets) [prescribing information]Year: 2006Merck and Co., IncWhitehouse Station, NJ
28.. Diovan® (valsartan) Tablets [prescribing information]Year: 2008Novartis Pharmaceuticals CorporationEast Hanover, NJ
29.. Julius S,Kjeldsen SE,Weber M,et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trialLancetYear: 200436394262022203115207952
30.. McMurray J. Angiotensin receptor blockers and myocardial infarction: analysis of evidence is incomplete and inaccurateBMJYear: 20053307502126915920134
31.. Opie LH. Angiotensin receptor blockers and myocardial infarction: direct comparative studies are neededBMJYear: 200533075021270127115920136
32.. Lewis EJ. Angiotensin receptor blockers and myocardial infarction: results reflect different cardiovascular states in patients with types 1 and 2 diabetesBMJYear: 200533075021269127015920133
33.. Tsuyuki RT,McDonald MA. Angiotensin receptor blockers do not increase risk of myocardial infarctionCirculationYear: 2006114885586016923769
34.. Yousef ZR,Leyva F,Gibbs C. Angiotensin receptor blockers and myocardial infarction: cautions voiced are biologically credibleBMJYear: 200533075021270127115920135
35.. Verdecchia P,Angeli F,Gattobigio R,Reboldi GP. Do angiotensin II receptor blockers increase the risk of myocardial infarction?Eur Heart JYear: 200526222381238616081468
36.. McDonald MA,Simpson SH,Ezekowitz JA,Gyenes G,Tsuyuki RT. Angiotensin receptor blockers and risk of myocardial infarction: systematic reviewBMJYear: 2005331752187316183653
37.. Volpe M,Mancia G,Trimarco B. Angiotensin II receptor blockers and myocardial infarction: deeds and misdeedsJ HypertensYear: 200523122113211816269950
38.. Cheung BM,Cheung GT,Lauder IJ,Lau CP,Kumana CR. Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertensionJ Hum HypertensYear: 2006201374316121197
39.. Messerli FH,Bangalore S,Ruschitzka F. Angiotensin receptor blockers: baseline therapy in hypertension?Eur Heart JYear: 200930202427243019723696
40.. Walker E,Hernandez AV,Kattan MW. Meta-analysis: Its strengths and limitationsCleve Clin J MedYear: 200875643143918595551
41.. Suzuki H,Kanno Y. Effects of candesartan on cardiovascular outcomes in Japanese hypertensive patientsHypertens ResYear: 200528430731416138560
42.. Yusuf S,Teo KK,Pogue J,et al. Telmisartan, ramipril, or both in patients at high risk for vascular eventsN Engl J MedYear: 2008358151547155918378520
43.. Yusuf S,Teo K,Anderson C,et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trialLancetYear: 200837296441174118318757085
44.. McMurray JJ,Holman RR,Haffner SM,et al. Effect of valsartan on the incidence of diabetes and cardiovascular eventsN Engl J MedYear: 2010362161477149020228403
45.. Sawada T,Yamada H,Dahlöf B,Matsubara H. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART StudyEur Heart JYear: 200930202461246919723695
46.. Mochizuki S,Dahlof B,Shimizu M,et al. Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality studyLancetYear: 200736995711431143917467513
47.. Massie BM,Carson PE,McMurray JJ,et al. Irbesartan in patients with heart failure and preserved ejection fractionN Engl J MedYear: 2008359232456246719001508
48.. Yusuf S,Diener HC,Sacco RL,et al. Telmisartan to prevent recurrent stroke and cardiovascular eventsN Engl J MedYear: 2008359121225123718753639
49.. Cohn JN,Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failureN Engl J MedYear: 2001345231667167511759645
50.. Schrader J,Luders S,Kulschewski A,et al. Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES)StrokeYear: 20053661218122615879332
51.. Goldstein MR,Mascitelli L,Pezzetta F. Angiotensin-receptor blockade, cancer, and concernsLancet OncolYear: 201011981781820816375
52.. Kanehira T,Tani T,Takagi T,Nakano Y,Howard EF,Tamura M. Angiotensin II type 2 receptor gene deficiency attenuates susceptibility to tobacco-specific nitrosamine-induced lung tumorigenesis: involvement of transforming growth factor-b-dependent cell growth attenuationCancer ResYear: 200565177660766516140932
53.. Clere N,Corre I,Faure S,et al. Def iciency or blockade of angiotensin II type 2 receptor delays tumorigenesis by inhibiting malignant cell proliferation and angiogenesisInt J CancerYear: 2010127102279229120143398
54.. Meredith PA,McInnes GT. Angiotensin-receptor blockade, cancer, and concernsLancet OncolYear: 201011981920816377
55.. Lithell H,Hansson L,Skoog I,et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trialJ HypertensYear: 200321587588612714861
56.. Bangalore S,Kumar S,Kjeldsen SE,et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomised trialsLancet OncolYear: 2011121658221123111
57.. The ARB Trialists CollaborationEffects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials enrolling 138 769 individualsJ HypertensYear: 201129462363521358417
58.. Huang CC,Chan WL,Chen YC,et al. Angiotensin II receptor blockers and risk of cancer in patients with systemic hypertensionAm J CardiolYear: 201110771028103321256465
59.. FDA Drug Safety CommunicationOngoing safety review of the angiotensin receptor blockers and cancerYear: 2010 Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformation-forPatientsandProviders/ucm218845.htm. Accessed March 2011..
60.. Tekturna® (aliskiren) Tablets, Oral [prescribing information]Year: 2010Novartis Pharmaceuticals CorporationEast Hanover, NJ
61.. Atacand® (candesartan cilexetil) Tablets [prescribing information]Year: 2009AstraZeneca LPWilmington, DE
62.. Avapro® (irbesartan) Tablets [prescribing information]Year: 2007Bristol Myers Squibb Sanofi-Synthelabo PartnershipNew York, NY
63.. Micardis® (telmisartan) Tablets [prescribing information]Year: 2009Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT
64.. Teveten® (eprosartan mesylate) Tablets [prescribing information]Year: 2007Abbott LaboratoriesNorth Chicago, IL
65.. Benicar® (olmesartan medoxomil) Tablets [prescribing information]Year: 2009Daiichi Sankyo, Inc.Parsippany, NJ
66.. Solomon SD,Wang D,Finn P,et al. Effect of candesartan on cause-specific mortality in heart failure patients: the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programCirculationYear: 2004110152180218315466644
67.. Pfeffer MA,Swedberg K,Granger CB,et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programmeLancetYear: 2003362938675976613678868
68.. McMurray JJ,Ostergren J,Swedberg K,et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trialLancetYear: 2003362938676777113678869
69.. Granger CB,McMurray JJ,Yusuf S,et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trialLancetYear: 2003362938677277613678870
70.. Yusuf S,Pfeffer MA,Swedberg K,et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved TrialLancetYear: 2003362938677778113678871
71.. Pfeffer MA,McMurray JJ,Velazquez EJ,et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or bothN Engl J MedYear: 2003349201893190614610160
72.. McMurray J,Solomon S,Pieper K,et al. The effect of valsartan, captopril, or both on atherosclerotic events after acute myocardial infarction: an analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT)J Am Coll CardiolYear: 200647472673316487836
73.. Dahlöf B,Devereux RB,Kjeldsen SE,et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenololLancetYear: 20023599311995100311937178
74.. Dickstein K,Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist LosartanLancetYear: 2002360933575276012241832
75.. Berl T,Hunsicker LG,Lewis JB,et al. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathyAnn Intern MedYear: 2003138754254912667024
76.. Brenner BM,Cooper ME,de Zeeuw D,et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathyN Engl J MedYear: 20013451286186911565518
77.. Pitt B,Poole-Wilson PA,Segal R,et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial--the Losartan Heart Failure Survival Study ELITE IILancetYear: 200035592151582158710821361

Article Categories:
  • Review

Keywords: angiotensin II receptor blocker, renin-angiotensin system, aliskiren, safety, myocardial infarction, cancer.

Previous Document:  Cardiovascular dysfunction in obesity and new diagnostic imaging techniques: the role of noninvasive...
Next Document:  Hepatocyte nuclear factor 4 alpha P2 promoter variants associate with insulin resistance.