An overview of candesartan in clinical practice

Abstract

Hypertension is a major risk factor for coronary heart disease, stroke, heart failure and renal disease. The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure 7 defined hypertension as a blood pressure of more than 140/90 mmHg and recommended to initiate treatment with a two-drug combination for stage 2 hypertension (blood pressure of 160-179/100-109 mmHg). The need for drug combinations is clear from a patient and physician perspective as they provide more effective blood pressure lowering, reduce pill burden, improve compliance and decrease hypertension-related morbidity and mortality. Angiotensin II receptor blocker therapy has been proven to be well tolerated and effective in the management of hypertension, chronic heart failure with left ventricular dysfunction and the prevention and progression of diabetic renal disease. Blockers of the renin-angiotensin system are an important component of antihypertensive combination therapy. Thiazide-type diuretics are usually added to increase the blood pressure lowering efficacy. Fixed drug-drug combinations of both principles, such as candesartan/hydrochlorothiazide, are highly effective in lowering blood pressure while providing improved compliance, a good tolerability and largely neutral metabolic profile. In this article, we review the literature for the role of candesartan-based therapy for hypertension, stroke, diabetes mellitus and heart failure.

Rationale for combination therapy

The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC)7 [1] and the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) [2] guidelines recommended consideration of combination treatment for patients with blood pressure (BP) more than 20/10 mmHg above target.

Since there are multiple pressor mechanisms contributing to hypertension, blockade of two pathways simultaneously should be more effective than blockade of a single pathway. The two agents should block different mechanisms. Ideally, one may block a mechanism that limits the full efficacy of the other. For example, diuretics block the sodium chloride and fluid retention that is often associated with the use of vasodilators and which limits their antihypertensive actions. Moreover, the effect of one agent may reduce the adverse effects of the other. For example, a distal potassium-sparing diuretic may block the hypokalemic effect of a thiazide diuretic. Examples of logical and well-established drug combinations for hypertension include an ARB or an ACE inhibitor (ACEI) combined with a thiazide diuretic. The American Society of Hypertension as well as the ESH guidelines consider combination of a β blocker with a thiazide diuretic as second choice. All of these drugs counteract the effects of the reactive increase in renin, angiotensin and aldosterone induced by the diuretic [3], thereby increasing the effectiveness in lowering BP and diminishing the adverse effects of aldosterone-induced potassium losses.

Furthermore, doses of coadministered drugs are generally lower than those required when the components are used individually [4]. A once-daily dose formulation of a drug combination facilitates compliance. An important predicted advantage of fixed-dose combinations is that patients will achieve their BP goal more quickly after initiation of therapy. This reduces the time that a patient’s BP is not controlled and thereby should reduce the cardiovascular (CV) complications of hypertension. Thus, a meta-analysis of 11,000 patients from trials that compared combination regimens with monotherapy concluded that those that employed a combination regimen were five-times more effective in reducing BP than those in which the dose of a single treatment was increased [5]. The Aliskerin and the Calcium-Channel Blocker Amlodipine Combination as an Initial Treatment Strategy for Hypertension (ACCELERATE) trial reported that BP reduction was 25% greater over the first 6 months in the patients receiving combination therapy with aliskiren and amlodipine compared with patients receiving only one drug and even at the end of the trial when all patients were receiving both drugs, the BP was still lower in those who started on combination therapy [6]. This indicates that not only does BP fall more quickly with combination therapy, but that this early advantage can persist for up to 6 months during trial conditions.

The number of antihypertensive agents required for BP control in recent trials has averaged two to four. Patients with comorbid conditions such as kidney disease or diabetes mellitus (DM) may require even more [7,8]. For example, an average of 3.3 drugs were required in the Hypertension Optimal Treatment (HOT) study to achieve the goal diastolic BP (DBP) of less than 80 mmHg [8]. In total, 78% of patients in the Anglo-Scandinavian Cardiac Outcomes Trial-BP Lowering Arm (ASCOT-BPLA) required two or more antihypertensive agents by the end of the trial [9].

Candesartan

Candesartan is an ARB that is administered orally as candesartan cilexetil. Its oral bioavailability is only approximately 40%, due to incomplete absorption. It is rapidly and completely converted to the active compound candesartan during absorption from the upper GI tract [10].

Candesartan is reported to have the highest receptor affinity of the available ARBs and is not displaced from the receptor by high concentrations of angiotensin II (Ang II) and therefore is an effective insurmountable antagonist [11,12]. This tight and long-lasting binding of candesartan to the angiotensin type 1 (AT1)-receptor provides highly effective blockade of the negative CV effects of Ang II. It diminishes the problem that occurs when patients miss taking their dose and provides effective blockade even at high concentrations of Ang II.

Candesartan is cleared predominantly by the kidneys and to a smaller extent by biliary or intestinal routes [13]. The effective half-life of candesartan cilexetil is longer than the plasma half-life of 4-9 h, reflecting its tight and prolonged binding to the receptor in the target tissues [14].

Effect of candesartan on high BP

Oral monotherapy with candesartan resulted in reduced placebo-corrected mean systolic BP (SBP) by 6.0 mmHg at 4 mg, 9.6 mmHg at 8 mg and 12.4 mmHg at 16 mg [15,16]. The placebo-corrected reduction in mean sitting DBP measured 24-h post-dose were 4.0 mmHg at 4 mg, 6.0 mmHg at 8 mg and 7.8 mmHg at 16 mg [15,16].

A direct comparison of 16 mg candesartan with 20 mg enalapril showed that candesartan was significantly more effective in reducing SBP and DBP (−13.5/−8.7 versus −9.9/−5.8 mmHg; p = 0.008) [17].

A head-to-head 8-week comparison of candesartan and losartan in patients with hypertension demonstrated that 8 mg of candesartan reduced the DBP by 8.9 mmHg, whereas 50 mg of losartan reduced the DBP significantly less by 3.7 mmHg (p = 0.013) [18]. Lacourciere et al. reported that the reduced BP was well preserved 36 h after a missed dose of 16 mg candesartan whereas the BP was not significantly reduced 36 h after a missed dose of 100 mg losartan [19].

These differences in effectiveness may reflect the long effective tissue half-life of candesartan.

Effect of combination of candesartan & hydrochlorothiazide on BP

Fixed-dose combinations of candesartan and hydrochlorothiazide (HCTZ) are available in various doses. The extent of BP reduction with candesartan/HCTZ in trials has depended on baseline BP and the dose. Combinations of 2, 4, 6, 8, 16 or 32 mg of candesartan with 6.25, 12.5 or 25 mg HCTZ, have been contrasted with monotherapy in placebo-controlled clinical trials in patients with hypertension [20-25].

Uen et al. studied the effect on 24 h ambulatory BP of replacing antihypertensive drugs that were not effective in achieving BP goal by candesartan/HCTZ in patients with hypertension. They reported that the combined therapy reduced SBP (148/81 vs 137/753 mmHg; p < 0.0015) and also reduced ST-segment depression in those with ECG evidence of myocardial ischemia [22]. Edes reported results from a randomized, double-blind trial and concluded that reductions in SBP and DBP were significantly greater (21/14 mmHg) with candesartan/HCTZ 32/25 mg than with candesartan 32 mg alone (13/9 mmHg), HCTZ 25 mg alone (12/8 mmHg) or placebo (4/3 mmHg; p < 0.001 for all comparisons) [23]. The proportion of patients with controlled BP (SBP <140 mmHg and DBP < 90 mmHg) at the end of this study was also significantly greater in the candesartan/HCTZ group (63%) than in the other treatment groups (p < 0.001 for all comparisons).

Bönner evaluated the efficacy of candesartan 32 mg in combination with HCTZ 12.5 or 25 mg in patients not optimally controlled using candesartan monotherapy in 3521 patients with treated or untreated hypertension and sitting DBP of 90-114 mmHg [26]. After a single-blind run-in phase (2 weeks candesartan 16 mg followed by a 6-week treatment with candesartan 32 mg), 1975 patients who still had DBP readings of 90-114 mmHg were randomized for an 8-week period of double-blind treatment with either candesartan 32 mg alone or candesartan 32 mg in combination with HCTZ 12.5 mg. Mean BP (153/97 mmHg at baseline) was reduced further during the double-blind phase by 6.1/5.6 mmHg in the candesartan monotherapy group, by 13.0/8.8 mmHg in the fixed combination of candesartan with HCTZ 12.5 mg group and by 15.5/10.0 mmHg in the fixed combination of candesartan with HCTZ 25 mg group (p < 0.01 for all between-treatment comparisons).

Bönner et al. tested first-line use of candesartan/HCTZ (16/12.5 mg) in an open-label, single-group study in 166 patients with newly diagnosed hypertension who had no prior antihypertensive pharmacotherapy for 6 weeks [20]. BP was reduced by 38/29 mmHg on average. In total, 40% of patients achieved normal BP. The first-line combination therapy with candesartan and HCTZ was well tolerated and very effective.

Effects of combination of candesartan & calcium-channel blocker

The Nifedipine and Candesartan Combination (NICE-Combi) study was a double-blind, parallel arm, randomized clinical trial, targeting men 20-70 years of age with mild-to-severe hypertension, who were not sufficiently controlled by conventional doses of candesartan monotherapy [27]. After discontinuation of previous antihypertensive treatments other than candesartan, 331 eligible patients received candesartan 8 mg for 8 weeks (baseline treatment period). Of this cohort (331 patients), a total of 258 patients (males: 147; females: 111) who were not sufficiently controlled by candesartan monotherapy were randomized for 8 weeks to receive candesartan 8 mg plus controlled-release nifedipine 20 mg (130 patients) or candesartan 12 mg for 8 weeks (128 patients). BP was reduced significantly in both groups (p < 0.05), but the reduction was significantly greater in the group randomized to combination therapy (12.1 ± 1.4/8.7 ± 0.9 mmHg) than in the uptitrated monotherapy group (4.1 ± 1.4/4.6 ± 0.9 mmHg; p < 0.0001). This was accompanied by a greater reduction in pulse pressure in the combination therapy group (3.3 ± 1.2 mmHg) than in the uptitrated monotherapy group (0.7 ± 1.2 mmHg; p = 0.0031).

Candesartan & prehypertension

Prehypertension affects over 30% of the adult population [28]. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High BP (JNC7) defined prehypertension as SBP 120-139 mmHg or DBP 80-89 mmHg [1]. It emphasized weight control and exercise as the mainstay of therapy, except for higher risk people such as those with DM, chronic kidney disease and known coronary artery disease, who may require drug therapy.

The Trial of Preventing Hypertension (TROPHY) [29] recruited people with ‘high normal BP’ who were randomized to 4 years of placebo (n = 381) or 2 years of 16 mg daily of candesartan (n = 391) followed by 2 years of placebo (Table 1). At the end of the 2-year period there was a 27% absolute and a 66% relative risk reduction (p < 0.0001) of hypertension in the candesartan-treated group. At study end, the former candesartan-treated group had a 10% absolute and a 16% relative risk reduction (p < 0.007) of hypertension. The treatment was well tolerated. This is the first trial of pharmacological intervention in people with prehypertension. It has stimulated debate about this approach, owing to the clinical and financial implications of treating over one third of the adult population [28, 30]; larger scale clinical outcome trials are needed before this can be widely advocated.

Table 1. Summary of candesartan outcome studies.

Study (year)	Drug	Control group	Population studied	Primary end point	Primary end point results	Statistical significance	Ref.
SCOPE (2003)	Candesartan	BB, CCB or diuretic	Patients 70-89 years of age with hypertension	CV death; nonfatal MI; nonfatal stroke; all stroke	RRR: 11%; RRR: 27.8%; RRR: 23.6%	95% CI: −6-25.1; p = 0.19; 95% CI: 1.3-47.2; p = 0.04; 95% CI: −0.7-42.1; p = 0.056	[36]
CHARM- Added (2003)	Candesartan	Placebo	HF: systolic dysfunction who were receiving ACEIs	CV mortality and HF hospitalization	HR: 0.85	95% CI: 0.75-0.96; p = 0.011	[31]
CHARM- Alternative (2003)	Candesartan	Placebo	HF: systolic dysfunction who were intolerant of ACEIs	CV mortality and HF hospitalization	HR: 0.77	95% CI: 0.67-0.89; p = 0.0004	[33]
CHARM- Preserved (2003)	Candesartan	Placebo	HF with preserved LVEF (>40%), with or without background ACE	CV mortality and HF hospitalization	HR: 0.89	95% CI: 0.77-1.03; p = 0.118	[34]
Direct Prevent 1 (2008)	Candesartan	Placebo	Type 1 diabetics without retinopathy who were normotensive and normoalbuminuric	Incidence of retinopathy	HR 0.82	95% CI: 0.67-1.00; p = 0.0508	[52]
Direct Protect 1 (2008)	Candesartan	Placebo	Type 1 diabetes and mild-to-moderate retinopathy	Progression of retinopathy	HR 1.02	95% CI: 0.80-1.31; p = 0.85	[52]
Direct Protect 2 (2008)	Candesartan	Placebo	Type 2 diabetics with retinopathy who were normoalbuminuric and normotensive or treated hypertensive	Progression of retinopathy; regression of retinopathy	HR: 0.87; HR: 1.34	95% CI: 0.70-1.08 p = 0.20; 95% CI: 1.08-1.68; p = 0.009	[51]
CASE-J (2008)	Candesartan	Amlodipine	High-risk hypertensive Japanese patients	CV events; decrease in LV mass index; new onset diabetes	HR 1.01: −22.9 g/m2 in candesartan vs 13.4 g/m2; RRR: 36%	95% CI: 0.79-1.28; p = 0.969; p = 0.023; p = 0.030	[46]
TROPHY (2006)	Candesartan	Placebo	High normal BP (systolic BP 130-139)	Development of hypertension	RRR: 15.6%	p < 0.007	[29]

ACEI: ACE inhibitor; BB: b-blocker; CASE-J: Candesartan Antihypertensive Survival Evaluation in Japan; CCB: Calcium-channel blocker; CHARM: Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbity; CV: Cardiovascular; HF: Heart failure; HR: Hazard ratio; LV: Left ventricular; LVEF: Left ventricular ejection fraction; LVH: Left ventricular hypertrophy; MI: Myocardial infarction; RR: Relative risk; RRR: Relative risk reduction; SCOPE: Study on Cognition and Prognosis in the Elderly; TROPHY: Trial of Preventing Hypertension.

Candesartan in patients with congestive heart failure

The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) [31] was a series of randomized, controlled studies designed to investigate the benefits of candesartan in three distinct populations of patients with symptomatic coronary heart failure (CHF): those with systolic dysfunction who were receiving ACEIs (CHARM-Added; n = 2548 [32]), those with systolic dysfunction who were intolerant of ACEI (CHARM-Alternative; n = 2,028) [33] and those with preserved left ventricular (LV) systolic function with or without background ACEI use (CHARM-Preserved; n = 3,023) [34]. The primary objective in each trial was to evaluate the effects of candesartan on the combined primary end point of CV mortality or hospitalization for CHF (Table 1).

Patients randomized to candesartan over 34 months in CHARM-Alternative (candesartan given instead of an ACEI) had a relative risk reduction (RRR) of 23% in composite end points (adjusted p < 0.0001), which resulted in a number needed to treat (NNT) of 14 [33].

Patients randomized to receive candesartan in addition to ongoing ACEI therapy for 41 months in the CHARM-Added trial had a 15% RRR in composite end points of CV mortality and hospitalization for heart failure (p = 0.010), which resulted in a NNT of 25 [32]. However, adverse events resulted in discontinuation of candesartan in 24% of patients compared with 18% in the placebo group (p = 0.0003).

Patients randomized to candesartan over 37 months in the CHARM-Preserved trial did not have a significant reduction in hospitalizations for CHF [34].

These trial results demonstrate the efficacy of candesartan therapy in patients with various categories of CHF and impaired LV function. Patients also require diuretic therapy to address edema. Most patients will require a loop diuretic for volume control but HCTZ can be used in select CHF patients in an initial dose of 25 mg and a maintenance dose of 25-100 mg daily [35].

Candesartan & stroke

The efficacy of candesartan in preventing stroke was tested in the Study on Cognition and Prognosis in the Elderly (SCOPE) and Acute Candesartean Cilexetil Therapy in Stroke Survivors Study (ACCESS) trials (Table 1).

The SCOPE randomized 4964 patients aged 70-89 years to a double blind comparison of candesartan or placebo with openlabel antihypertensive therapy (mostly thiazide diuretics) added as needed to control BP [36]. Approximately 35% of patients had isolated systolic hypertension (SBP: 160-179 mmHg and DBP < 90 mmHg). BP fell by 22/11 mmHg in the candesartan group and by 19/10 mmHg in the control group. Candesartan-based therapy was associated with a nonsignificant 10.9% RRR in the primary composite end point of CV death, nonfatal stroke and nonfatal myocardial infarction (242 vs 268 events). There were significant reductions in nonfatal stroke (27.8%; p = 0.04) and a trend for a reduction in all strokes (23.6%; p = 0.056) but no differences in myocardial infarction and CV mortality. The significant reduction in nonfatal stroke could be due to the lower BP achieved in the candesartan group.

In a predefined subgroup analysis of patients with isolated systolic hypertension, candesartan-based therapy resulted in a 42% risk reduction in stroke (p = 0.049 adjusted for baseline risk) despite no significant difference in BP control [37].

The Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study was a Phase II multicenter double-blind placebo-controlled trial in 500 patients designed to assess the safety of modest BP reduction by candesartan in the early treatment of stroke [38]. The trial was stopped prematurely when 342 patients had been randomized owing to an imbalance in end points. Candesartan treatment for 7 days, started within 24 h of stroke onset, reduced the cumulative 12-month mortality (7.2 vs 2.9%) and vascular events (18.7 vs 9.8%). The groups were well matched for CV risk factors and BP at study onset and within the study period. The authors concluded that early initiation of low-dose candesartan was safe and likely beneficial in patients with acute stroke. However, these strikingly positive results with candesartan were not confirmed in the much larger Prevention Regimen For Effectively avoiding Second Strokes (PRoFESS®) trial of telmisartan in the management of acute stroke [39].

The ARB candesartan for treatment of acute stroke (SCAST) trial was a randomized, placebo-controlled, double-blind study in which 2029 patients with acute stroke (ischemic or hemorrhagic) and SBP of 140 mmHg or higher were randomized within 30 h of symptom onset to candesartan (n = 1017) versus placebo (n = 1012) [40]. During the 7-day treatment period, BPs were significantly lower in patients allocated to candesartan than in those on placebo (mean: 147/82 mmHg [SD: 23/14] in the candesartan group on day 7 vs 152/84 mmHg [22/14] in the placebo group; p < 0.0001). During 6 months’ followup, the risk of the composite vascular end point did not differ between treatment groups (candesartan, 120 events, vs placebo, 111 events; adjusted hazard ratio: 1.09; 95% CI: 0.84-1·41; p = 0.52) Analysis of functional outcome suggested a higher risk of poor outcome in the candesartan group (adjusted common odds ratio: 1.17; 95% CI: 1.00-1.38; p = 0.048 [not significant at p ≤ 0.025 level]) There was no indication that careful blood-pressure lowering treatment with the ARB candesartan is beneficial in patients with acute stroke and raised BP. In fact, it may even have a harmful effect.

Candesartan & DM, albuminuria & retinopathy

Post-hoc analysis of clinical trials have suggested that drugs that block the renin-angiotensin-aldosterone system (RAAS) may reduce the onset of DM [41]. RAAS blockade may improve the delivery of insulin and glucose to peripheral skeletal muscle or improve insulin release or insulin responsiveness, perhaps secondary to increased plasma potassium concentration, thereby improving insulin sensitivity [42]. Candesartan reduced the number of patients developing DM in the CHARM, SCOPE, and Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE) trials [36,43,44].

A systematic review [45] identified 48 randomized groups in 22 clinical trials with 143,153 participants who did not have DM at randomization. The association of antihypertensive drugs with incident DM was lowest for ARBs and ACEIs, followed by calcium-channel blockers and placebo and followed by β-blockers and diuretics, which appear to increase the risk.

The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) randomized 4728 Japanese patients at high risk for CV events to candesartan and amlodipine [46]. The number of CV events was similar in both groups among those with strict BP control (<140/80 mmHg). However, those randomized to candesartan had a significantly greater decrease in LV mass index over 3 years in those with pre-existing LV hypertrophy (−23 vs −13.4 g/m²; p = 0.023) and a significant reduction in new-onset DM (RRR: 36% p = 0.03). In a subgroup of patients with a BMI of 25 kg/m² and higher, the incidence of new-onset DM was 47% lower in the candesartan than the amlodipine treatment group (p = 0.03). CHARM evaluated new-onset DM as a secondary end point [47]. A total of 163 (6.0%) patients in the candesartan group developed DM over 2-4 years, compared with 202 (7.4%) in the placebo group (RRR: 28%; p = 0.020). The composite end point of death or DM occurred in 692 (25.2%) and 779 (28.6%) of the candesartan and placebo groups, respectively (HR: 0.86; 95% CI: 0.78-0.95; p = 0.004). This is an unusual end point selection and while these studies of secondary end points or post-hoc analysis have provided some support for the hypothesis that RAAS blockade reduced the development of new-onset DM, recent large-scale trials that have evaluated this as a primary end point have failed to confirm this.

The Diabetes Reduction Approaches with Ramipril and Rosiglitazone Medications (DREAM) trial randomized 5269 participants with impaired glucose tolerance without CV disease to ramipril (up to 15 mg per day) or placebo for a period of 3 years [48]. Composite outcome of DM or death did not differ significantly between the ramipril group (18.1%) and the placebo group (19.5%; hazard ratio: 0.91; 95% CI: 0.81-1.03; p = 0.15) however participants receiving ramipril were more likely to have regression to normoglycemia than those receiving placebo (hazard ratio: 1.16; 95% CI: 1.07-1.27; p = 0.001). The Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial randomized 9306 patients with impaired glucose tolerance and established CV disease or CV risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification [49]. The three coprimary outcomes were the development of DM; an extended composite outcome of death from CV causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. The cumulative incidence of DM was 33.1% in the valsartan group, compared with 36.8% in the placebo group (HR in the valsartan group: 0.86; 95% CI: 0.80-0.92; p < 0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended CV outcome (14.5 vs 14.8%; HR: 0.96; 95% CI: 0.86-1.07; p = 0.43) or the core CV outcome (8.1 vs 8.1%; HR: 0.99; 95% CI: 0.86-1.14; p = 0.85).

Among patients with impaired glucose tolerance and CV disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of DM but did not reduce the rate of CV events.

Microalbuminuria in DM is predictive of nephropathy, end-stage renal disease and premature CV morbidity and mortality. The effect of candesartan in the prevention of microalbuminuria was tested in a pooled analysis of the Effect of Candesartan on Prevention and Progression of Retinopathy in Type 1 Diabetes (DIRECT) trial program, which included normotensive patients with Type 1 (n = 3326) and Type 2 (n = 1905) DM. The incidence of microalbuminuria was low and although no differences in the risk for albuminuria were noted, the annual rate of change in albuminuria was 5.5% lower (95% CI: 0.73-10.14%; p = 0.024) with candesartan than with placebo [50]. The DIRECT trial consisted of three randomized, double-blind, placebo-controlled multicenter studies designed to investigate whether candesartan could halt the progression of or possibly prevent the development of diabetic retinopathy [51, 52]. Candesartan had a beneficial outcome for patients with Type 2 DM who had established mild-to-moderate retinopathy, in whom candesartan had a BP-independent improvement in retinopathy.

Conclusion

The reviewed data in this article demonstrate that candesartan-based combination for hypertension and CHF with reduced ejection fraction is an effective therapy. In addition, target BP is faster and more easily reached with combination treatment than with monotherapy. The candesartan-based combination therapy has been demonstrated to be well tolerated across several important subgroups of patients including those with DM and heart failure.

Expert commentary

Candesartan and candesartan/HCTZ has been demonstrated to be both safe and effective in the treatment of severe hypertension [53,54]. The CHARM trial demonstrated that patients with a reduced ejection fraction.

The TROPHY study showed that candesartan could reduce the chances of developing hypertension in prehypertension subjects. However, larger scale clinical outcome trials are needed before this can be widely advocated. Candesartan was also effective in reducing strokes in the SCOPE trial and in reducing new-onset DM in the CHARM trial.

The Candesartan and Lisinopril Microalbuminuria (CALM) trial reported a larger reduction in BP with the combination of candesartan and lisinopril than with monotherapy and greater reduction in albuminuria [55]. The Renal Outcomes With Telmisartan, Ramipril, or Both, In People at High Vascular Risk (ONTARGET) trial studied ramipril and telmisartan alone and in combination in a mixed population of patients with a history of CV disease or high-risk Type 2 DM [56]. The trial reported a reduction in proteinuria with combination therapy but with no overall benefit in terms of CV outcomes and at the expense of greater side effects, including hypotension and worsening renal function.

Overall, this extensive clinical trial data indicate that candesartan is a safe, well-tolerated ARB whose efficacy may be further enhanced when given as combination therapy.

Five-year view

Combination therapies will play an increasingly important role for optimal BP control. Combination therapy has the potential to increase compliance and the JNC7 [1] and the ESH [2] guidelines recommend consideration of combination treatment for patients with BP more than 20/10 mmHg above target. Furthermore, doses of coadministered drugs are generally lower than those required when the components are used individually [4]. An important predicted advantage of fixed-dose combinations is that patients will achieve their BP goal more quickly after initiation of therapy. This reduces the time that the patient’s BP is not controlled and thereby should reduce the CV complications of hypertension [6].

Key issues.

• Hypertension is a major risk factor for coronary heart disease, stroke, heart failure and renal disease.

• The Joint National Committee 7 recommended initiating treatment with a two-drug combination for stage 2 hypertension.

• Candesartan is an ARB with high affinity for the angiotensin type 1 receptors.

• Clinical trials have demonstrated that the majority of patients with hypertension require combination therapy with two or more agents to achieve blood pressure goal.

• Candesartan hydrochlorothiazide-based therapy is very effective in the treatment of hypertension and is well tolerated.

• Candesartan reduced cardiovascular mortality by 23% in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative study and also reduced hospitalization for coronary heart failure in patients with a reduced ejection fraction.