By Meredith, Peter A
Key words: Candesartan – Cardiovascular disease – Heart failure – Hypertension ABSTRACT
Therapeutic interventions that block the renin-angiotensin- aldosterone system (RAAS) have an important role in slowing the progression of cardiovascular risk factors to established cardiovascular diseases. In recent years, angiotensin receptor blockers (ARBs) have emerged as effective and well-tolerated alternatives to an anglotensin-converting enzyme Inhibitor (ACEi) for RAAS blockade. The ARB candesartan was initially established as an effective once-daily antihypertensive treatment, providing 24-h blood pressure (BP) control with a trough:peak ratio close to 100%.
Scope: A Medline literature search was undertaken to identify randomised, controlled trials that examined the efficacy and cardiovascular outcomes associated with candesartan cilexetil in hypertension and chronic heart failure (CHF).
Findings: Compared with other ARBs, candesartan demonstrates the strongest binding affinity to the angiotensin II type 1 receptor. Clinical trials have demonstrated that candesartan Is well tolerated in combination with diuretics or calcium channel blockers (CCBs), making it a suitable treatment option for patients whose hypertension is not adequately controlled by monotherapy. Subsequently, candesartan became the only ARB licensed in the UK to treat patients with CHF and left ventricular ejection fraction = 40% as add-on therapy to an ACEi or when an ACEi is not tolerated. Studies in patients with symptomatic HF have indicated that candesartan treatment was associated with significant relative risk reductions in cardiovascular mortality and hospitalisation due to CHF.
Conclusions: There are clear indications that the clinical benefits of candesartan may extend beyond its proven antihypertensive effects to a wider range of complications across the cardiovascular continuum, including diabetes, left ventricular hypertrophy, atherosclerosis and stroke. Such results suggest that candesartan treatment may offer significant patient benefits as well as practical advantages over conventional treatment.
Introduction
The cardiovascular (CV) continuum
According to the most recent analysis of the global burden of disease and risk factors, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide1, despite the fact that advances in diagnosis and management have resulted in a decline in the incidence and mortality of coronary heart disease (CHD) and stroke in the developed world2. In contrast, however, levels of heart failure (HF) are increasing in both incidence and prevalence, as well as in overall mortality3. CVD may be regarded as a continuum, which begins when risk factors initiate progressive tissue damage and structural changes such as atherosclerosis and left-ventricular hypertrophy (LVH). Further deterioration leads to myocardial infarction (MI) and left-ventricular dysfunction, before reaching the end-stage of severe HF, and eventual death (Figure 1)4- 6.
Hypertension is a major risk factor for CVD, and the most common risk factor for the development of HF7. Clinical trials have shown that lowering blood pressure (BP), regardless of the drug used to achieve this, remains the key variable in preventing future CV events8. The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) has been widely criticised due to perceived methodological failings9, but nevertheless, the trial results helped to clarify the importance of optimising antihypertensive therapy to reduce CVD risk and development of HF10. In addition, data from the Valsarian Antihypertensive Long-Term Use Evaluation (VALUE) study showed reductions in the incidence of cardiac events in patients in whom BP was controlled compared with those in whom it was not11. Therefore, if HF represents the end of the CV continuum, then it may be said that hypertension represents the beginning.
The RAAS system
The renin-angiotensin-aldosterone system (RAAS) is involved at all stages of CVD12. Angiotensinogen is cleaved by renin to form inactive angiotensin I, which is in turn converted into active angiotensin II by an angiotensin-converting enzyme (ACE) (Figure 2). Subsequent activation of the angiotensin II type 1 (AT^sub 1^) receptor results in elevated BP, while over-activation leads to the development of hypertension and CVD12. Activated AT^sub 1^ also leads to the formation of reactive oxygen species, oxidative stress and endothelial dysfunction, and ultimately to atherosclerosis13. The role of the AT^sub 2^ receptor is less well defined, but it appears to mediate vasodilation via a bradykinin/ nitric oxide cascade, and may also act to inhibit renin biosynthesis and secretion, providing a short-loop negative feedback mechanism to dampen angiotensin II production (Figure 2)14.
Figure 1. The cardiovascular continuum. Adapted with permisnon4. Copyright Elsevier, 1991
RAAS blockade may, therefore, provide benefit at all stages of CVD. Although early pharmacological interventions relied on the use of an ACE inhibitor (ACEi) to inhibit angiotensin II15-17, there is theoretical and practical evidence that a more complete inhibition can be achieved by the use of angiotensin II receptor antagonists (ARBs), which prevent binding of angiotensin II to the AT^sub 1^ receptor18-21. Furthermore, ARBs are not associated with the most common adverse effects experienced with an ACEi, the bradykinin- mediated cough22-23, and are commonly associated with cutaneous eruptions/rash24,25, proteinuria and renal failure26,27, and angioedema28,29. ARBs are extremely well tolerated30,31, and the evidence available to date suggests that patient compliance with treatment protocols is higher with ARBs than with other antihypertensive agents, which is a key factor in achieving adequate BP control20,32.
Although a number of ARBs have been approved for the treatment of hypertension, this review will focus on candesartan cilexetil, and the increasing evidence base supporting its use as a cardioprotective agent. Currently, candesartan is the only ARB licensed in the UK to treat both hypertension and chronic HF (CHF). It may be reasonable to assume, therefore, that the clinical benefits of candesartan may extend to other aspects of CVD ranging across the CV continuum33. This paper will review the current evidence on the use of candesartan in hypertension and CHF, and attempt to establish whether there may be additional benefits in treating patients with concomitant complications such as microalbuminuria, atherosclerosis and stroke. A Medline literature search was undertaken to identify randomised, controlled trials that examined the efficacy and cardiovascular outcomes associated with candesartan cilexetil in hypertension and CHF.
Figure 2. The renin-angiotensin-aldosterone system. Angiotensin II, the principal effector of the renin-angiotensin system mediates most of the relevant biological effects by activation of the angiotensin II type-1 (AT^sub 1^) receptor. ACE: angiotensin- converting enzyme; AT^sub 2^ receptor: angiotensin II type-2 receptor; B^sub 1^ receptor: bradykinin type-1 receptor; B^sub 2^ receptor: bradykinin type-2 receptor; NO: nitric oxide. Reproduced with permission12
Candesartan in hypertension
Choosing an antihypertensive agent
A sustained and consistent BP-lowering effect is a key consideration in the choice of antihypertensive agent, since 24-h BP control can not only address the problem of poor patient compliance (delayed or missed dosing)21, but also there is a sound rationale for smooth and consistent BP control to improve CVD outcomes34,35. Duration of action is described by mathematical indices such as the trough:peak ratio (a measurement of BP reduction at the end of the dose interval and before the next dose is administered, relative to BP reduction at the time of the maximal drug effect)36. Optimum control is provided by drugs with a trough:peak ratio of >/= 50% and preferably close to 100%37.
Since its launch, almost 10 years ago, a wealth of data has accumulated, detailing the efficacy and tolerability of candesartan. Initially developed as an antihypertensive agent, candesartan provides effective 24-h BP control, with a trough:peak ratio close to 100%38-40. Candesartan provides a significant, dose-dependent, antihypertensive effect in prescribed amounts at a dose range of 2- 32 mg once daily in hypertension of all grades, with good tolerability in all age groups and genders, and no dose-related adverse effects41-46.
Comparison with losartan
The majority of head-to-head comparisons between candesartan and other ARBs involve losartan, as this was the first agent of its class to be approved for the treatment of hypertension and thus represents a benchmark against which other ARBs are compared. Candesartan has consistently shown BP-lowering efficacy results equal or superior to those of losartan, even from the very earliest studies38,47.
In an 8-week study comparing the antihypertensive effects of candesartan and losartan, patients with hypertension (sitting diastolic BP [DBP] 95-114mmHg) were randomised between four treatment groups, and treated once daily with either losartan 50 mg (n = 83), candesartan cilexetil 8 mg (n = 82), candesartan cilexetil 1 6 mg (n = 84) or placebo (n = 85)39. BP was measured at 6 h and 24 h after dosing (at peak and trough), and the primary effect variable was trough sitting DBP. The results of the study showed that candesartan had a similar tolerability profile to placebo, and significantly reduced trough DBP at both dosage concentrations (p
Comparison with other ARBs
In vitro studies have shown that candesartan acts as an insurmountable, tightly-bound antagonist, and is able to virtually eliminate the AT^sub 1^ receptor-mediated effects of angiotensin II49. Compared with other ARBs, candesartan demonstrates the strongest binding affinity to the AT^sub 1^ receptor50, approximately 80-fold higher than losartan and 10-fold higher than EXP 3174, the active metabolite of losartan51. This insurmountable antagonism provides long-lasting suppression of the RAAS and accounts for candesartan’ s significant antihypertensive efficacy.
Figure 3. Mean changes from baseline in ambulatory blood pressure during 36h after dose in patients treated with candesartan (8-1 6 mg) or losartan (50-100 mg). Reproduced with permission48 . Copyright Elsevier, 1999
A meta-analysis by Elmfeldt et al. examined the relationships between dose and antihypertensive effect of four ARBs: losartan, valsartan, irbesartan and candesartan52. Importani differences in the antihypertensive efficacy between the drugs at their highest recommended doses (losartan 1 50 mg; valsartan 320 mg; irbesartan 300 mg; candesartan 32 mg) were observed (Figure 4). Overall, treatment with candesartan results in a higher maximal achievable effect on trough DBP (7.5 mmHg, 95% CI 6.1-8.9), compared with all of the other ARBs (losartan 5.6, 95% CI 3.6-7.5; valsartan 5.8, 95% CI 5.0-6.6; irbesartan 6.9, 95% CI 5.9-7.9). When comparing the effects of candesartan against valsartan, this reduction in DBP is significant (p= 0.014). Such results are supportive of other head- to-head comparisons, in which candesartan has been shown to be more efficacious than losartan and valsartan in reducing BP53,55. In an 8- week comparison of candesartan 8 mg/day (starting and maintenance dose) and olmesartan 20 mg/day (optimal dose), 26% of mild-moderate hypertensive patients taking olmesartan achieved a 24-h BP goal of
Figure 4. Dose-response curves for the effect of different angiotensin receptor blockers on trough diastolic blood pressure in hypertensive patients. Adapted with permission52
Comparison with other antihypertensive agents
ACE inhibitors
In head-to-head trials, the antihypertensive activity of candesartan has been shown to be as effective as lisinopril57,58 and enalapril59-62. However, according to results from The Effect duration of Enalapril versus Candesartan cilexetil Treatment (EffECT) study, candesartan has a superior duration of action to enalapril63. In this 8-week trial, patients with primary hypertension were randomised to receive either 8-1 6 mg candesartan (n = 196) or 10-20mg enalapril (n = 1 94) once daily, with ABP measurements taken for 36 h at baseline and after the 8-week treatment period. At 8 weeks, mean reductions from baseline in systolic and diastolic ABP (3 6 h after dosing) in hypertensive patients treated with candesartan 1 6 mg were significantly greater than with enalapril 20 mg (SBP -15.7mmHg vs -11.6, p = 0.013; DBP – 9.8mmHg vs -7.2, p = 0.009). In addition, the duration of efficacy was greater for candesartan, with a trough:peak ratio of 76%, compared with 38% for enalapril63.
Another investigation found that candesartan reduced BP more effectively and was better tolerated than enalapril in women with mild-to-moderate hypertension64. In this 12-week trial, women were randomised to receive 8-1 6 mg of candesartan (n = 140) or 10-20 mg of enalapril (n = 146) once daily for 12 weeks. Candesartan reduced seated BP to a greater extent than enalapril (p
Calcium channel blockers (CCBs)
The efficacy of candesartan is also comparable with CCBs, such as amlodipine, a long-acting dihydropyridine CCB that has been shown to be effective and well tolerated in patients with hypertension65,66. In the first study, after a 4-week placebo run-in period, patients with primary hypertension were randomised to once-daily treatment with either candesartan 8 mg (n = 85) or amlodipine 5 mg (n = 84), or placebo (n = 83) for 8 weeks65. Both active-treatment regimens resulted in significant reductions in sitting and standing BP compared with placebo (p
Combination treatments
ARB/HCTZ diuretic
Many patients will require combination therapy to adequately control BP to targets recommended by UK guidelines67,68. Thiazide diuretics, such as hydrochlorothiazide (HCTZ) are now available in once-daily, single-tablet formulations in combination with various ARBs, promoting patient compliance as well as providing effective hypertensive therapy69. However, in line with data demonstrating that candesartan monotherapy is more effective than losartan in treating patients with hypertension39,48, two randomised clinical trials have also shown that the combination of candesartan 16mg/ HCTZ 12.5 mg is more effective than losartan 50mg/HCTZ 12.5 mg in reducing BP70,71. In the CAndesartan/HCTZ veRsus LOSartan/HCTZ (CARLOS) study, patients (n = 160) were randomised between the two treatments for 6 weeks, with BP measured at baseline and at the end of the treatment period. The mean differences in antihypertensive effect between candesartan/HCTZ and losartan/HCTZ at 24 h post-dose were systolic -8.4/diastolic -6.2 mmHg in favour of the candesartan combination treatment (p
ARB/CCB
In a randomised study, patients given a placebo run-in period for 4 weeks were subsequently assigned to once-daily treatment with candesartan 8 mg (n = 85), amlodipine 5 mg (n = 84), the combination (n = 89) or placebo (n = 83) for 8 weeks65. Sitting and standing BP was measured at the time of randomisation and at 8 weeks. All active treatment regimens resulted in marked reductions in BP compared with placebo (p
A small-scale (n = 31) investigation into the effects of felodipine, candesartan or the combination on BP control in elderly hypertensive patients, was also able to show that the combination treatment reduced mean 24-h BP to a significantly greater extent than either of the monotherapies (p
Although the concomitant use of ARBs with an ACEi in hypertension is not currently recommended by any substantive guidelines, diere is a theoretical rationale to suggest a complementary benefit from such a combination. There is evidence to suggest that treatment with candesartan and lisinopril maybe slightly more effective in reducing BP tiian either treatment alone73″76.
In the Candesartan And Lisinopril Microalbuminuria (CALM) I study, 199 patients with hypertension and Type 2 diabetes with microalbuminuria were randomised to candesartan 16 mg/day or lisinopril 20 mg/day for 1 2 weeks, followed by a further 1 2 weeks with eidier monotherapy or a combination of the two treatments77. Both monotherapies showed equivalent BP reduction compared with baseline [p
Target groups
In elderly patients, the control of SBP is particularly important, since (unlike DBP) this continues to increase with age78. If left untreated, isolated systolic hypertension can increase the risk of developing CV disease, whilst treatment has been shown to reduce mortality, stroke and HF events79,80.
An early study to evaluate the antihypertensive efficacy and tolerability of candesartan (n = 97) versus placebo (n = 96) in elderly (> 65 years) patients concluded that treatment with 8 or 1 6 mg candesartan cilexetil was effective and well tolerated81. After 1 2 weeks of treatment, the mean placebo-corrected reduction in supine DBP was 7.5 mmHg (95% CI 3.6-1 1.4; p
The Study on COgnition and Prognosis in the Elderly (SCOPE) study was designed to determine the effects of ATj-receptor blockade on CV and cognitive outcomes in elderly (aged > 70 years) patients with mild-to-moderate hypertension82. Although the study was originally conceived as a comparison of candesartan with placebo, changes to WHO-ISH guidelines, and a consequential protocol revision, resulted in a large proportion of patients (particularly in the placebo group) receiving additional antihypertensive medication83. Overall, the mean BP was reduced from baseline by 2 1.7 mmHg (SBP) and 10. 8 mmHg (DBP) in the candesartan-based treatment group (n = 2477), and by 18.5/9.2 in the control arm (n = 2460)83. The BP of patients receiving only once-daily candesartan 8-1 6 mg (n = 1253) or only placebo (n = 845) were analysed post-hoc over a mean follow-up period of 3.7 and 3.5 years, respectively84. The mean SBP/DBP was reduced by 21.8/1 1.0 mmHg in the candesartan treatment group, and by 17.2/8.4 mmHg in the placebo group. The difference in adjusted BP reductions between the two groups was 4. 7/2. 6 mmHg (p
The recently reported CHANCE study was an 8 week, open-label, multicentre study evaluating the efficacy and tolerability of candesartan (8-1 6 mg) in 3013 elderly (> 65 years) hypertensive patients85. BP control (SBP
Candesartan in HF
Candesartan also has an established role in the treatment of HF. The groundbreaking Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme was designed to directly address the major questions raised by other investigations into the use of ARBs in this patient population, such as the Valsartan Heart Failure Trial (VaIHeFT) and the losartan HF survival study (ELITE II), by comparing the effects of candesartan with placebo in three different patient groups86. Composed of three independent but concurrent, placebo-controlled trials (Figure 5), the CHARM studies evaluated whether the use of candesartan would reduce the risk of CV death or hospital admission for CHF, in patients with symptomatic HF87. CHARM-Alternative (n = 2028) compared candesartan with placebo in ACEi-intolerant patients with CHF (New York Heart Association [NYHA] class II-IV) and left ventricular ejection fraction (LVEF) 40%)90. Patients were randomised to candesartan (4-32 mg titration as tolerated) or matching placebo, and were followed for at least 2 years up to 4 years. The primary outcome for all trials was CV mortality or hospitalisation87, while secondary outcomes included, for example, effects on NYHA class, development of atrial fibrillation (AF) and incidence of a new diagnosis of diabetes.
In both CHARM-Alternative and CHARM-Added, significant relative risk reductions in the primary endpoint were observed in favour of candesartan, compared with placebo (23%, p = 0.0004 and 15%, p= 0.011, respectively)88,89 (Figure 6). Of those patients taking study medication at the 6-month visit, 63% receiving candesartan had achieved the target dose (32 mg once daily)87. In CHARM-Added, patients who were being treated with an ACEi at a constant dose (for 30 days or longer) were randomly assigned to receive candesartan (n = 1276) or placebo (n = 1272) once-daily89. In addition to the reduction in primary endpoint, the addition of candesartan provided a further clinically important reduction in relevant CV events in all predefined subgroups (including patients receiving a beta- blocker at baseline). Furthermore, post-hoc analysis has determined that these additional survival benefits occur irrespective of ACEi dose at baseline91. In CHARM-Alternative, patients who were not receiving an ACEi due to previous intolerance were randomised to receive candesartan (n = 1013) or placebo (n = 1015). During a median follow-up of 33.7 months, each component of the primary outcome was reduced in the candesartan treatment group, as was the total number of hospital admissions for CHF (candesartan 445 vs placebo 608; p = 0.0001)88.
To enable comparison with further landmark studies with ACEi and beta-blockers, pooled analysis of the low LVEF CHARM trials showed that fewer patients in the candesartan group (n = 817 [35.7%]) experienced CV death or a CHF hospitalisation as compared with 944 (41.3%) in the placebo group (hazard ratio [HR] 0.82, 95% CI 0.74- 0.90, ?
Figure 5. Schematic overview of the CHARM trials
Figure 6. Cumulative event curves for the primary outcome (CV death or hospital admission for chronic heart failure) in (A) CHARM- Alternative and (B) CHARM-Added. Reproduced with permission88,89 . Copyright Elsevier, 2003
The results of the CHARM study indicate that candesartan is generally well tolerated in patients with symptomatic CHF. More patients discontinued candesartan than placebo due to concerns about renal function, hypotension and hyperkalemia (797 [21.0%] vs 633 [16.7%]; p
Candesartan and CV complications
Diabetes
Type 2 diabetes is a common risk factor for the development of HF and an important factor in subsequent prognosis. There is an established link between diabetes and LVH, coronary artery disease and hypertension, and affected individuals are at increased risk of morbidity and mortality due to HF. Prevention of diabetes may, therefore, prevent or delay the development of many stages of the CV continuum, such as atherosclerosis and MI, whilst also improving the outcomes of those patients with symptomatic HF. In SCOPE, candesartan-based antihypertensive treatment, compared with control treatment, was associated with a relative reduction in new-onset diabetes of 19% (p = 0.09)83. This observation is consistent with candesartan-based treatment in the Antihypertensive treatment and Lipid Profile In a North of Sweden Efficacy evaluation (ALPINE) study94. In this study, 392 hypertensive patients, of whom 94% had received no previous antihypertensive drug treatment, were randomised to candesartan 16 mg (n = 197) or HCTZ 25 mg (n = 196) and followed for 1 year. Diabetes was diagnosed in nine patients during the follow-up period: eight in the HCTZ group (4.1%) and one (0.5%) in the candesartan group (p = 0.03). Candesartan treatment was also found to reduce newonset diabetes in the CHARM programme95. In the combined analysis of the three study arms, 163 (6.0%) patients in the candesartan group developed diabetes during the study, as compared with 202 (7.4%) in the placebo group (HR 0.78, 95% CI 0.64-0.96, p = 0.02).
Diabetic retinopathy
Retinopathy is a common complication of diabetes96,97 and a leading cause of blindness98. The Diabetic REtinopathy Candesartan Trials (DIRECT) programme has been designed to determine whether treatment with candesartan can prevent the incidence and progression of diabetic retinopathy99. Comprising three randomised studies of over 5000 patients with either Type 1 diabetes without diabetic retinopathy, or Type 1/2 diabetes with diabetic retinopathy, the DIRECT programme is expected to report in 2008100.
Renal disease
Diabetic nephropathy is a leading cause of end-stage renal disease with the most significant risk factors being hypertension and albuminuria101. Both irbesartan and losartan are licensed for use in diabetic nephropathy, and it is possible that the benefit conferred may be a class effect. In the Candesartan And Lisinopril Microalbuminuria (CALM) trial, candesartan (16 mg) and lisinopril (20 mg) were equivalent in reducing BP (adjusted mean difference between treatments for DBP 0.2 mmHg, 95% CI -2.3 to 2.7, p > 0.20; SBP 3.3 mmHg, 95% CI -1.5 to 8.2, p = 0.18) and microalbuminuria (adjusted mean difference in urinary albuminxreatinine ratio 30%, 95% CI 1 to 71; p = 0.058) in hypertensive patients with Type 2 diabetes. Dual RAAS blockade was well tolerated and more effective in reducing BP than with either single agent77. In a placebo- controlled study conducted in 80 chronic haemodialysis patients with no previous evidence of cardiac disorders, candesartan 4-8 mg/day was associated with a 16% cardiovascular event rate and a 0% mortality rate compared with 46% and 19% with placebo (p
LVH
Surrogate endpoint studies of CV structure and function are an alternative means of assessing the potential benefits of ARB therapy73,103. LVH is recognised as a risk factor for CV complications in hypertensive patients104,105. Markers such as LVH and arterial function are clinically relevant to prognostic outcomes and recent studies have shown that candesartan has beneficial effects on such endpoints.
The Candesartan Assessment in the Treatment of Cardiac Hypertrophy (CATCH) study compared the effects of candesartan (8-1 6 mg once daily) and enalapril (10-20 mg once daily) on LVH62. Both treatments were found to be equally effective in reducing BP and LVH (as determined by two-dimensional M-mode echocardiograms obtained at baseline and after 24 and 48 weeks of treatment). Candesartan reduced LVMI by 15.0g/m^sup 2^ (-10.9%; p
Stroke prevention
As well as increasing the risk of CV events, hypertension is also a risk factor for cognitive decline and dementia106-108. Evidence to suggest that ARBs have positive effects on stroke prevention has come from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study and SCOPE. In the LIFE study, losartan reduced the risk of stroke by 25% relative to atenolol, despite achieving equivalent BP control109. SCOPE supports and extends the results of LIFE83; untreated and previously treated elderly hypertensive patients were randomised to candesartan (8-1 6 mg) or placebo for a mean of 3.7 years, with other antihypertensives being added if BP was uncontrolled. The main analysis showed that non- fatal stroke was reduced by 28% (p = 0.04) in the candesartan group relative to control, and there was a non-significant 1 1 % reduction in the primary endpoint of major CV events (p = 0.19). Post-hoc analysis of a sub-group of patients not receiving add-on therapy showed significant risk reductions with candesartan in major CV events (32%; p = 0.013), CV mortality (29%; p = 0.049) and total mortality (27%; p = 0.018)84. Other analyses also suggested positive effects of candesartan on cognitive function83 and quality of life110. Both candesartan in SCOPE and losartan in LIFE are associated with reductions in stroke, however, it is not possible to definitively suggest that this was a benefit beyond BP reduction alone111. Trends towards CV benefit were observed in SCOPE.
The Acute Candesartan Cilexetil therapy in Stroke Survivors (ACCESS) study was designed to assess the safety of modest BP lowering in early stroke112. Compared with placebo (n = 167), a 7- day course of candesartan 4-1 6 mg (n = 175) after an acute ischaemic stroke was shown to significantly improve CV morbidity and mortality (candesartan 2.9% vs placebo 7.2%; p = 0.07), without the occurrence of any CV or cerebrovascular event (candesartan 9.8% vs placebo 18.7%; p = 0.026). The study was stopped early on the recommendation of the safety committee, since the cumulative 12- month mortality and the number of vascular events differed significantly in favour of the candesartan group (odds ratio 0.475, 95% CI 0.252-0.895). The role of candesartan in acute stroke is being further investigated in the Scandinavian Candesartan in Acute Stroke Trial (S-CAST)113.
Myocardial infarction
Despite significant reductions in BP, major trials of ARBs in high-risk patients have thus far failed to convincingly demonstrate reduction in MI and mortality, and rates of MI have actually increased in some trials evaluating ARBs88,114,115. The data for ARBs and MI, and the plausibility of BP-independent mechanisms through which ARBs might, or might not, potentially increase MI risk, have been the subject of recent debate116,117.
For example, a recent analysis found that ARBs increase the risk of MI mortality116. However, in the same journal issue, Tsuyuki and McDonald reported that ARB use was not associated with an increased risk of MI117. A systematic review of controlled trials found that the use of ARBs was not associated with significantly increased risk of MI in patients at risk for CV events, when compared with placebo (odds ratio 0.94, 95% CI 0.75-1.16) or ACEi (odds ratio 1.01, 95% CI 0.87-1. 16)118. The data regarding candesartan are also inconsistent. While CHARM-Alternative noted an increased risk of MI88, a reduced risk of MI was observed in CHARM-Added89. Currently, there is no consensus of opinion regarding ARBs and increased MI risk, although substantive evidence that ARBs can reduce MI is also lacking. Additional information from large, prospective trials (e.g. the ONTARGET telmisartan studies) will be available in the next few years and should clarify the relationship between ARBs and MI.
Atherosclerosis
Hypertension results in structural changes in large arteries, contributing to atherosclerosis and increased intima-media thickness (IMT). The effect of candesartan on vascular remodelling in large arteries has been studied in the Candesartan Atenolol Carotid Haemodynamics Endpoint Trial (CACHET)119. In patients treated for 52 weeks with candesartan 8-1 6 mg (n = 44) or atenolol 50-1 00 mg (n = 44), IMT was measured in the distal common carotid and carotid bulb by B-mode ultrasound at baseline and after 52 weeks of treatment. Both treatments produced similar regression of carotid IMT (candesartan -0.05 mm, atenolol -0.07 mm; p = 0.93), however, carotid blood flow was reduced in atenololtreated patients compared with the candesartan group (-1.6mL/s vs -0.4 mL/s; p
Atrial fibrillation
It is well recognised that AF increases the risk of CV complications120,121, and that hypertensive patients have an increased risk of developing AF121,122. Although the mechanisms leading to AF are complex, observations from the CHARM programme support the suggestion that the RAAS plays a role in its pathogenesis. The incidence of new AF was a pre-specified secondary outcome in the CHARM studies; at baseline, 6446 (84.8%) patients had no AF, as determined by ECG. During follow-up, 177 (5.55%) patients in the candesartan group and 215 (6.74%) patients in the placebo group developed AF (odds ratio 0.802, 95% CI 0.65-0.99; ? = 0.039)123. In addition, there was no heterogeneity of the effects of candesartan in preventing AF between the three component trials (p = 0.57). Regardless of baseline rhythm, candesartan improved clinical outcomes124. In a separate study, candesartan showed no effect compared with placebo on the recurrence rate of AF after electrical cardioversion125.
Discussion
All the evidence suggests that the majority of benefit derived from any antihypertensive drug is associated with BP lowering per se. It logically follows that tight and consistent BP control over a 24-h period with once-daily dosing, will maximise benefit by reducing CV and associated events. Furthermore, there is compelling evidence that well-tolerated agents improve long-term persistence with therapy, which itself is most likely to improve outcome. ARBs as a class have been shown to be the most well-tolerated antihypertensive agents and, based primarily on comparative studies using valsartan and losartan (and not longer-acting agents such as irbesartan and telmisartan), candesartan appears to be one of the most potent agents, with the longest duration of action within the class. This is apparent not only with monotherapy based upon BP lowering and attainment of BP control, but also with combination therapy, particularly the combination of candesartan with a diuretic or CCB. Beyond this focus on BP control there is compelling evidence that candesartan offers additional benefits that are apparent in a number of different ways. Some of these effects can be considered to be class effects, including prevention of new-onset diabetes, prevention of new onset AF, selective benefit in reducing left ventricular and vascular hypertrophy, a reduction in the development of renal impairment in diabetic nephropathy, and a selective benefit in primary and secondary stroke prevention. The potential benefits of candesartan in diabetic retinopathy are also being evaluated in a major outcome trial, DIRECT, and the results of tiiis trial are awaited with interest.
Finally, the CHARM programme provided unique data regarding the benefits of candesartan in HF. This was characterised by a reduction in hospitalisations and mortality in patients with impaired left ventricular function receiving an ACEi at optimal doses and in those patients who were ACEi-intolerant. A trend towards a similar benefit was also seen in those patients with preserved left ventricular function. These and otJier secondary findings from the CHARM programme clearly indicate that candesartan offers considerable benefit by way of reducing events and that this translates into economic benefit via cost-savings for healthcare systems and healthcare providers. It is imperative that treatments for a condition as common as CHF are affordable; a prospective economic analysis of the CHARM programme concluded that candesartan improves functional class, reduces the risk of hospital admission and increases survival in patients with CHF and LVEF
Conclusions
Despite evidence-based medicine being at the heart of hypertension guidelines, under-treatment of hypertension still remains a significant public health issue. Currently, treatment with an ACEi is the leading RAAS inhibitor therapy used, but data are now accumulating in favour of ARBs. Comparative results show the efficacy of ARBs to be similar or better than other classes of antihypertensive agent, without the associated side effects of an ACEi (cough, rash, angioedema) or the adverse metabolic effects seen with diuretic- and/or beta-blocker-based treatment.
The ARB candesartan has proven anti-hypertensive effects, but the clinical benefits of candesartan extend far beyond that of controlling BP. Candesartan is the only ARB licensed to treat patients with CHF with LVEF
With respect to its pharmacological activity, candesartan has been shown to be one of the most effective ARBs. It has demonstrated efficacy as an effective intervention at various levels of the cardiovascular continuum, and ongoing outcome trials are anticipated to confirm this potential.
Acknowledgements
The author has received honoraria for consultancy, advisory board attendance and speaker fees from a number of pharmaceutical companies, including AstraZeneca, Bayer, Boehringer-Ingelheim, GSK, MSD, Pfizer and Takeda. The author acknowledges medical writing assistance from Dr Sally Mitchell, supported by an unrestricted grant from Takeda. The views and opinions expressed herein are solely those of the author.
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