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which permits unrestricted noncommercial use, provided the original work is properly cited. Vascular Health and Risk Management 2009:5 10431058 Vascular Health and Risk Management 1043 R E V I E W Dovepress open access to scientic and medical research Open Access Full Text Article submit your manuscript | www.dovepress.com Dovepress Management of hypertension with fxed dose combinations of candesartan cilexetil and hydrochlorothiazide: patient perspectives and clinical utility Thomas Mengden 1
Sakir Uen 1
Peter Bramlage 2 1 Centre of Vascular Medicine, Herz- und Gef-Campus, Bad Nauheim, Germany; 2 Institute for Cardiovascular Pharmacology and Epidemiology, Mahlow, Germany Correspondence: Thomas Mengden Centre of Vascular Medicine, Herz- und Gef-Campus Bad Nauheim, Ludwigstrae 41, 61231 Bad Nauheim, Germany Tel +49 6032 9995906 Fax +49 6032 9995501 Email [email protected] Abstract: Hypertension treatment and control is largely unsatisfactory when guideline-dened blood pressure goal achievement and maintenance are considered. Patient- and physician-related factors leading to non-adherence interfere in this respect with the efcacy, tolerability, and convenient use of pharmacological treatment options. Blockers of the reninangiotensin system (RAS) are an important component of antihypertensive combination therapy. Thiazide-type diuretics are usually added to increase the blood pressure lowering efcacy. Fixed drugdrug combinations of both principles like candesartan/hydrochlorothiazide (HCTZ) are highly effective in lowering blood pressure while providing improved compliance, a good toler- ability, and largely neutral metabolic prole. Comparative studies with losartan/HCTZ have consistently shown a higher clinical efcacy with the candesartan/HCTZ combination. Data on the reduction of cardiovascular endpoints with xed dose combinations of antihypertensive drugs are however scarce, as are the data for candesartan/HCTZ. But many trials have tested candesartan versus a non-RAS blocking comparator based on a standard therapy including thiazide diuretics. The indications tested were heart failure and stroke and particular emphasis was put on elderly patients or those with diabetes. In patients with heart failure, for example, the xed dose combination might be applied in patients in whom individual titration resulted in a dose of 32 mg candesartan and 25 mg HCTZ which can then be combined into one tablet to increase compliance with treatment. Also in patients with stroke the xed dose combination might be used in patients in whom maintenance therapy with both components is considered. Taken together candesartan/HCTZ assist both physicians and patients in achieving long-term blood pressure goal achievement and maintenance. Keywords: chronic heart failure, stroke, diabetes, angiotensin receptor blocker, patients, physicians, persistence, compliance Background Hypertension is a highly prevalent risk factor for coronary heart disease (CHD), stroke, heart failure (HF), renal disease, and recurrent cardiovascular events. It has been shown to reduce the number of life-years lost and the number of years lived with disability by 64.3 million globally. 1 The European Society of Hypertension (ESH) classies optimal blood pressure at 120 mmHg systolic blood pressure (SBP), and 80 mmHg diastolic blood pressure (DBP). 2 A therapeutic reduction of elevated blood pressure (BP) levels has been shown to decrease cardiovascular morbidity and mortality. 3 For the pharmacological management Number of times this article has been viewed This article was published in the following Dove Press journal: Vascular Health and Risk Management 30 November 2009 Vascular Health and Risk Management 2009:5 1044 Mengden et al Dovepress submit your manuscript | www.dovepress.com Dovepress of hypertension, lowering BP below 140/90 mmHg in all patients is requested. Specic patients, those with diabetes mellitus or chronic kidney disease, need further BP reduction (130/80 mmHg or 125/75 mmHg, respectively). However these BP targets are difcult to meet despite the availability of a number of effective antihypertensive drugs. Consequently hypertension control is largely ineffective as the achievement of guideline dened treatment targets with about 20% of patients in Europe and up to 50% of patients in the US being nally controlled when treated. 4,5 BP target achievement is even worse in patients with comorbid disease like diabetes mellitus. Patient perspective Hypertension is a rather unspectacular disease with unspe- cic symptoms that are, from a patient perspective, in many cases not perceived to occur in relation to hypertension. Patients therefore are reluctant to accept physicians recom- mendations to adopt life-style changes (weight reduction, reduction of sodium intake, and increased physical activity), which are the recommended rst steps in the treatment of hypertension. It becomes even more difcult to convince patients for the need of action when antihypertensive pharmacotherapy is introduced. A number of patient-related factors leading to non- adherence like frequent dosing, 6,7 drug-related adverse events (AEs), 8 health beliefs, 9 drugdrug interactions and associated medical conditions interfere with the patients willingness to take drugs as prescribed. For an overview of terms used to describe adherence see Figure 1. Actually approximately half of the patients on antihypertensive drug therapy discontinue therapy by the end of the rst year. Hence, from a patient perspective, there is a need for effective, highly tolerable and convenient medication that does not interfere with daily life while controlling hypertension-associated risk. Physician perspective Recent data suggest that also physicians attitudes and treatment strategies hamper the effectiveness of current therapy. 1012 In a recent global survey in a random sample of primary care physicians, 41% of physicians aimed to reduce BP to acceptable levels only, although generally agreeing with guideline recommended treatment goals. Physicians further believed that 62% of their patients had their BP controlled. However, in fact only 6% of patients with hyper- tension in the UK had their BP lowered to the recommended levels. 13 In France, Germany, Italy, and Spain only 13% of hypertensive patients have their BP controlled. 14 The physicians needs in the treatment of hypertension are partially overlapping with patients needs. However, in the face of low patient compliance, the chronic nature of the disease, and increasing budget constraints, a possible solution seems to be difcult to determine. Treatment patterns Globally about one-third of patients receive monotherapy, one-third dual combination therapy, and one-third 3 or more Adherence Drug prescription Acceptance Discontinuation Visit Persistence (days) Compliance (% days with correct dosing) Figure 1 Terms used to describe adherence. Vascular Health and Risk Management 2009:5 1045 Candesartan cilexetil and HCTZ combination for hypertension Dovepress submit your manuscript | www.dovepress.com Dovepress antihypertensive drugs. The NICE for example calculated that 36% of patients in the UK receive monotherapy, 38% dual combination therapy, and 26% 3 or more drugdrug combinations. 15 In a recent drug utilization analysis in primary care in Germany, 29.2% of treated patients received one, 43.7% received 2, and 27.2% received 3 or more anti- hypertensive drugs. 16 According to the aforementioned study 16 40.8% of patients in Germany received ACE inhibitors (ACEi), 36.1% beta blockers, 31.7% diuretics, 22.3% calcium channel blockers (CCBs) and 14.1% angiotensin receptor blockers (ARBs). 16 Frequent drugdrug combinations were ACEi or ARBs in combination with diuretics, CCBs, and beta blockers which is mostly in accordance with recent guide- lines in which 4 out of 6 recommended combinations are ACEi/ARB based. 17 Guidelines The 2007 ESH/ESC guideline recognize 5 major antihy- pertensive drug classes thiazide diuretics, CCBs, ACEi, ARBs, and betablockers to be suitable for the initiation and maintenance of antihypertensive treatment. 17 The JNC VII guidelines 18 on the other hand recommend using thiazide diuretics rst. Both guidelines agree however in recommend- ing the use of particular drug classes based on the presence of compelling indications. ACEi and ARBs are recommended for the largest variety of compelling indications (for a detailed overview see Table 1), with only minor compelling contraindications in patients with pregnancy, hyperkalemia, bilateral renal artery stenosis, and angioneurotic edema (ACEi only). Therefore both drug classes are used, as illustrated by data from different drug utilization studies, 16,19 in 50% to 60% of patients. Drugdrug combination therapy According to the ESH/ESC guidelines, 17 the following drugdrug combinations have been found to be effective and well tolerated in randomized efcacy trials: Thiazide diuretic plus ACEi, thiazide diuretic and ARB, CCB and ACEi, CCB and ARB, CCB and thiazide diuretic, and beta blocker and dihydropiridine CCBs. Thus, 4 out of 6 recom- mended dual antihypertensive combinations are ACEi/ARB based (Figure 2). The ACCOMPLISH study triggered a lively discussion about the relative importance of drugdrug combinations. 20,21
It was designed to test whether benazepril 40 mg combined with amlodipine 10 mg would result in stronger cardiovas- cular event reduction than benazepril 40 mg/HCTZ 25 mg. Inclusion and exclusion criteria favored the selection of patients with compelling indications for the use of CCBs. The composite primary endpoint of cardiovascular morbidity and mortality was reduced by 19.6% in patients receiving benazepril/amlodipine versus benazepril/HCTZ (9.6 versus 11.8%; hazard ratio [HR] 0.80, 95% CI 0.720.90). The secondary endpoint of death from cardiovascular causes, non-fatal myocardial infarction, and non-fatal stroke was reduced by 21% with a HR of 0.79 (95% CI 0.670.92). Side effects were generally however more frequent with amlodipine than with the thiazide diuretic. Unfortunately no similar comparative study of the ACCOMPLISH type exists for patients with compelling indications for thiazide diuretic use. 22 At present the evidence base is weak for deciding which patient would benet the most from either combination. Law and Wald have suggested combining ACEi/ARBs with a low dose of any of the other drug classes to maximize BP lowering efficacy while maintaining a placebo-like tolerability. 23 This recommendation was based on the meta- analytic observation that both ACEi and ARBs maintain a particular low AE prole in doses up to 4 times standard dose. On the contrary all other drug classes (CCBs, betablockers, thiazides) showed a steep incline of side effects at higher doses, while the tolerability was good at half-standard or even at standard dose. The common approach to control BP in hypertensive patients is to titrate monotherapy to full dose and to add another agent if BP is still high (Figure 3, green). Drugs might be exchanged if there is indication of non-response to a particular agent. More recently the ESH/ESC guidelines 17
introduced the concept of rst-line combination therapy at low dose in patients with marked BP elevation, low target BPs, and high or very high cardiovascular risk (Figure 3, red). This has been shown to be effective and safe and tolerability of rst-line combination therapy is excellent. 24,25 Requirements for antihypertensive drugs In summary, from a patient, physician, and societal perspective there is a clear need for drugdrug combinations which provide effective BP lowering, and display a low side effect prole and a high adherence of both physicians and patients with treatment. This would enable BP control to be increased considerably and would in turn not only save on hypertension-related morbidity (stroke, ischemic heart disease) and mortality but also on costs. It has been calculated for the UK that achieving a systolic BP of 140 mmHg on a large scale would decrease stroke Vascular Health and Risk Management 2009:5 1046 Mengden et al Dovepress submit your manuscript | www.dovepress.com Dovepress Table 1 Compelling indications and contraindications in the use of antihypertensive drug classes 17
Conditions favoring use Compelling or possible contraindications Thiazide diuretics Isolated systolic hypertension (elderly) Gout Heart failure Metabolic syndrome Hypertension in blacks Glucose intolerance Pregnancy Beta blockers Angina pectoris Asthma Post-myocardial infarction A-V block (grade 2 or 3) Heart failure Peripheral artery disease Tachyarrhythmias Metabolic syndrome Glaucoma Glucose intolerance Pregnancy Athletes and physically active patients Chronic obstructive pulmonary disease Calcium antagonists (dihydropyridines) Isolated systolic hypertension (elderly) Tachyarrhythmias Angina pectoris Heart failure LV hypertrophy Carotid/coronary atherosclerosis Pregnancy Hypertension in blacks Calcium antagonists (verapamil/diltiazem) Angina pectoris A-V block (grade 2 or 3) Carotid atherosclerosis Heart failure Supraventricular tachycardia ACE inhibitors Heart failure Pregnancy LV dysfunction Angioneurotic edema Post-myocardial infarction Hyperkalemia Diabetic nephropathy Bilateral renal artery stenosis Non-diabetic nephropathy LV hypertrophy Carotid atherosclerosis Proteinuria/microalbuminuria Atrial fbrillation Metabolic syndrome Angiotensin receptor antagonists Heart failure Pregnancy Post-myocardial infarction Hyperkalemia Diabetic nephropathy Bilateral renal artery stenosis Proteinuria/microalbuminuria LV hypertrophy Atrial fbrillation Metabolic syndrome ACEi-induced cough Diuretics (antialdosterone) Heart failure Renal failure Post-myocardial infarction Hyperkalemia Loop diuretics End stage renal disease Heart failure Vascular Health and Risk Management 2009:5 1047 Candesartan cilexetil and HCTZ combination for hypertension Dovepress submit your manuscript | www.dovepress.com Dovepress incidence by up to 44% depending on age group considered and ischemic heart disease incidence up to 35%. 15 Assuming that a reduction of stroke incidence of 9% and ischemic heart disease of 4% across age groups might actually be achievable, the annual saving to the NHS would be 255 million for stroke and 25 million for ischemic heart disease while investing 58 million into drugs (net benet to the NHS 222 million) (Figure 4). Candesartan/HCTZ The xed drugdrug combination of candesartan cilexetil in a dose up to 32 mg and HCTZ in a dose up to 25 mg fulls Thiazide diuretics -blockers -blockers ACE inhibitors Calcium antagonists Angiotensin receptor antagonists Figure 2 Four out of 6 recommended dual antihypertensive combination therapies include blockers of the reninangiotensin system. Notes: Red, recommendation including an angiotensin receptor blocker; green, recommendations including an ACE inhibitor. Reproduced with permission from Mancia G, De Backer G, Dominiczak A, et al. Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007; 25(6):11051187. 17 Copyright Lippincott Williams & Wilkins. Choose between Mild BP elevation Low/moderate CV risk Conventional BP target Single agent at low dose Previous agent at full dose Switch to different agent at low dose If goal BP not achieved If goal BP not achieved Previous combination at full dose Add a third drug at low dose Two-drug combination at low dose Two- to three-drug combination at full doses Two- to three-drug combination at full dose Marked BP elevation High/very high CV risk Lower BP target Full dose monotherapy Figure 3 Combination therapy as an escalation option and as frst-line therapy. Notes: Green, 2-drug combination therapy as an option for treatment escalation; red, 2-drug combination as a frst line option in patients with marked elevation of blood pressure and high cardiovascular risk. Reproduced with permission from Mancia G, De Backer G, Dominiczak A, et al. Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007; 25(6):11051187. 17 Copyright Lippincott Williams & Wilkins. Vascular Health and Risk Management 2009:5 1048 Mengden et al Dovepress submit your manuscript | www.dovepress.com Dovepress most of the above-mentioned requirements for improving BP control and related morbidity on a larger scale. Candesartan Candesartan is an ARB that is administered orally as candesartan cilexetil; it is rapidly and completely converted to candesartan, the active compound, during absorption from the upper gastrointestinal tract. 26 It is characterized by a strong binding afnity to the angiotensin II type 1 receptor and its slow dissociation. Its binding to the AT 1 receptor is insurmountable, meaning that it cannot be overcome by high concentrations of angiotensin II and, under physiological conditions, may even not dissociate until the AT 1 receptor is recycled. 26 Twenty-four hours after administration to healthy volun- teers, the angiotensin II inhibiting activity per milligram of candesartan was stronger than that shown by other ARBs. 27
The trough-to-peak ratio is almost 90% (mean of all doses available). After a missed dose of candesartan, losartan, or placebo, 48-hour post-dose signicant reductions of BP have been observed with candesartan 16 mg daily but not with losartan or placebo. 28 Candesartan, applied as oral monotherapy, results in a strong dose-dependent reduction of both SBP and DBP between 4 and 16 mg, levelling off at 32 mg, and reaching its maximum at 8 weeks after treatment initiation. 29,30 In a direct comparison of 16 mg candesartan and 20 mg enalapril candesartan was signicantly more effective in reducing SBP and DBP (13.5/8.7 versus 9.9/5.8 mmHg; P = 0.008). 31
It was also shown that BP returned to baseline after a missed dose of enalapril (7.2/4.5 mmHg) earlier than after a missed dose of candesartan (11.4/8.0 mmHg; P = 0.0002). Candesartan (up to 16 mg) and losartan (up to 50 mg) were compared in an 8-week study. 32 Candesartan reduced diastolic BP by 8.9 and 10.3 mmHg with the 8 and 16 mg doses, respectively, while the BP reduction with losartan 50 mg was 3.7 mmHg, the latter comparison reaching statistical signicance (P = 0.013). Twenty-four hours after the ingestion of candesartan 100% of the peak SBP/DBP lowering effect was preserved (trough/peak ratio about 100% both systolic and diastolic) while only 70% of the losartan effect was preserved (trough/peak ratio 70% both systolic and diastolic). 32 These data were essentially conrmed by Lacourciere et al which also demonstrated, that after a missed dose of 16 mg candesartan, the effect was well preserved after 36 hours, while the effect of 100 mg losartan was signicantly reduced. 28 It is tempting to speculate that differences in effectiveness of these ARBs may reect pharmacologic and pharmacoki- netic differences. The elimination half-life of candesartan is longer than that of losartan and its active metabolite. Candesartan cilexetil produces clear dose-dependent anti- hypertensive effects, whereas it has been difcult to dem- onstrate this property for losartan. 26,32 Hydrochlorothiazide HCTZ mainly acts within the lumen of the distal nephron, blocking the luminal transmembrane-coupled sodium chloride transport system. The mechanism by which thiazide diuretics reduce BP is however not completely understood. It has been proposed that during long-term therapy, thiazides act by reducing total peripheral resistance probably through a direct vascular effect. 33 It is important to note however that in vivo vasodilation was achieved at higher doses than those reached during long-term oral treatment. 34 HCTZ treatment in patients with hypertension induced changes in Additional drug costs 58.4 million Savings from reduced IHD 25.2 million Savings from reduced stroke/IHD 280.4 million Net savings from intensified treatment 221.9 million Savings from reduced stroke 255.1 million Figure 4 Cost savings in the UK by intensifying antihypertensive drug treatment. 15 Notes: Optimizing antihypertensive therapy in the UK will cost 58.4 million and will prevent costs due to prevented stroke/ischemic heart disease (IHD) of 280.4 million resulting in a net beneft of 221.9 million. Vascular Health and Risk Management 2009:5 1049 Candesartan cilexetil and HCTZ combination for hypertension Dovepress submit your manuscript | www.dovepress.com Dovepress plasma volume, cardiac output, mean arterial pressure, stroke volume, heart rate, and total peripheral resistance. 33,35 HCTZ has a half-life of 8 to 15 hours on chronic use and a duration of action that is slightly longer. 36 HCTZ 50 mg twice daily for 12 or 36 weeks, after a 4-week placebo run-in period, lowered mean arterial pressure in 13 patients with untreated essential hypertension and DBP 100 mmHg. 35
Compared with the mean baseline value (177.2 mmHg), these reductions were significant throughout the study duration. BP reduction with candesartan/HCTZ versus placebo Fixed dose combinations of candesartan and HCTZ are available in various doses. Candesartan 32 mg once daily has to be regarded as a high dose (4 times standard dose). 23
HCTZ 12.5 and 25 mg have to be regarded as a half-standard and standard dose, respectively. Therefore the available combinations full the requirements suggested by Law and Wald 23 for maximizing efcacy while maintaining a high tolerability. The extent of BP reduction with candesartan/HCTZ depends on baseline BP and the dose used. A variety of combinations including 2, 4, 6, 8, 16, or 32 mg candesartan and 6.25, 12.5, or 25 mg HCTZ, respectively, has been tested in clinical trials versus respective monotherapies or placebo. 25,3741 Uen et al for example demonstrated that replacing previously ineffective antihypertensive drugs by candesartan/HCTZ in patients with uncontrolled arterial hypertension signicantly reduced both BP and ST-segment depression during daily life. 41 Taken together these studies have consistently shown that combinations of candesartan with HCTZ, administered orally once a day for 4 to 52 weeks, induced signicant reductions in SBP and DBP from baseline in patients with mild, moderate, or severe hypertension. In a recent study by Edes et al (baseline DBP 90114 mmHg), mean reductions in SBP and DBP were signicantly greater with candesartan 32/HCTZ 25 mg (21/14 mmHg) 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). 39 The proportion of patients with controlled BP (SBP 140 mmHg and DBP 90 mmHg) at the end of this study was also signicantly greater in the candesartan 32/HCTZ 25 mg group (63%) than in the other treatment groups (P 0.001 for all comparisons). Bnner investigated the efcacy of candesartan 32 mg in combination with HCTZ 12.5 or 25 mg in patients not optimally controlled using candesartan monotherapy. 42 A total of 3521 patients with treated or untreated hypertension and sitting DBP of 90 to 114 mmHg were included. 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 to 114 mmHg were randomized to an 8-week double-blind treatment with either candesartan 32 mg alone or in combination with HCTZ 12.5 mg or 25 mg respectively. Mean BP (153/97 mmHg at baseline) was further reduced during the double-blind treatment phase by 6.1/5.6 mmHg in the candesartan monotherapy group, by 13.0/8.8 mmHg in the xed combination with HCTZ 12.5 mg group, and by 15.5/10.0 mmHg in the xed combination with HCTZ 25 mg group (P 0.01 for all between treatment comparisons) (Figure 5). Bnner et al tested the first-line use of candesartan 16 mg/HCTZ 12.5 mg in 166 patients with no prior phar- macotherapy for a treatment duration of 6 weeks. 25 Blood pressure was reduced by 38.1/29.4 mmHg with 40% of patients achieving a normalization of BP. Tolerability was good showing that rst line combination therapy is feasible and safe. BP reduction with candesartan/HCTZ versus losartan/HCTZ Ohma et al compared xed dose combinations of candesartan 16/HCTZ 12.5 mg and losartan 50/HCTZ 12.5 mg in patients insufciently controlled on previous monotherapy. 43 BP at randomization was 159.5/98.4 mmHg and 160.5/98.5 mmHg, respectively. After 12 weeks there was a greater reduction of BP with candesartan/HCTZ (19.4/10.4) than with losartan/HCTZ (13.7/7.8 mmHg), the differences being statistically signicant. Twelve patients withdrew in the candesartan/HCTZ group (8 due to AEs), and 17 in the losartan/HCTZ group (12 AEs). Knig compared candesartan/HCTZ and losartan/HCTZ in a 6-week study. 44 Twenty-four-hour postdose mean seated BP was reduced by 32.2/21.1 mmHg (systolic/diastolic) in the candesartan/HCTZ group and 23.8/14.9 mmHg in the losartan/HCTZ group (P 0.001). Blood pressure reductions 48 hours postdose were 25.6/16.4 mmHg for candesartan/ HCTZ and 9.2/4.2 mmHg for losartan/HCTZ, with differ- ences between treatments being highly signicant in favor of candesartan/HCTZ (16.5/12.2 mmHg; P 0.001). Both treatments were well tolerated. Tolerability/compliance ARBs are generally regarded to be a drug class with high compliance/persistence. 45 Persistence with antihypertensive Vascular Health and Risk Management 2009:5 1050 Mengden et al Dovepress submit your manuscript | www.dovepress.com Dovepress medication (including candesartan) was compared between different drug classes and between substances within one drug class in an Australian analysis covering the years 2004 to 2006. 46 The database yielded information relating to 48,690 patients prescribed antihypertensive medication. The median persistence time was 20 months, which was also the median persistence with ARBs or ACEi. The median persistence with CCBs was considerably lower (median persistence time 7 months; -57%, P 0.001). There were further differences in persistence between indi- vidual drugs in the respective classes, the best outcomes being with candesartan and telmisartan (10%20% better than the other ARBs considered), perindopril (ACEi; 25% better other ACEi) and lercanidipine (CCB; 25% better than other CCBs). This high persistence was reected in the recent DIRECT trial in that about 80% of patients were compliant with 32 mg candesartan even when being nominally normotensive. 47,48 Candesartan/HCTZ is generally well tolerated in patients with mild to moderate hypertension. Combined data from 5 randomised, double-blind, placebo-controlled clinical trials indicated that AEs during candesartan/HCTZ therapy (up to 16 mg/25 mg once daily) are uncommon and only few were serious. 49 Among patients receiving candesartan/HCTZ or placebo the incidence of serious AEs was 1.6 and 2.1%, respectively, while 3.3 and 2.7% of patients discontinued treatment because of AEs. The most common AEs were headache, back pain, dizziness, and respiratory infections. Recent trials indicated that the AE prole of candesartan 32 mg in combination with 12.5 or 25 mg HCTZ is comparable to the aforementioned observations. 39,42 Bnner et al reported about 1% serious AEs that were independent of whether monotherapy with candesartan or combination therapy including HCTZ was considered. For metabolic parameters, a slight increase of serum ureate and serum creatinine was observed with the xed combinations while other parameters were essentially unchanged (Table 2). 42
Edes et al reported a rate of serious AE for the xed dose combination that was even lower compared to placebo (0.2% versus 3.1%), with overall AE rate ranging between 23% and 25% for placebo, HCTZ, candesartan, and their combination. 39 Mengden et al compared drug regimen compliance (DRC) with antihypertensive combination therapy in patients whose BP was controlled versus uncontrolled after 4 weeks of self-monitored BP measurement. 50 Whether switching one drug of the combination therapy to candesartan/HCTZ (16 mg/12.5 mg) in uncontrolled patients with and without compliance intervention program would improve BP normal- ization was also evaluated. It was found that normalization of BP was associated with superior drug regimen compliance in previously uncontrolled patients treated with a combina- tion drug regimen. Switching still-uncontrolled patients to 18.0 16.0 14.0 12.0 10.0 8.0 6.0 4.0 2.0 0.0 Candesartan 32 mg Candesartan 32/HCTZ 12.5 mg Candesartan 32/HCTZ 25 mg SBP DBP Figure 5 Blood pressure reduction with 32 mg candesartan alone or in combination with 12.5 or 25 mg HCTZ in patients not suffciently controlled on monotherapy. 42 Vascular Health and Risk Management 2009:5 1051 Candesartan cilexetil and HCTZ combination for hypertension Dovepress submit your manuscript | www.dovepress.com Dovepress candesartan/HCTZ signicantly improved BP control and stabilized a declining DRC. Patient types Patients with heart failure Heart failure is a frequent comorbidity in patients with hypertension. It is characterized by a decline in systolic or diastolic function, the latter being a typical complication of long-term uncontrolled hypertension. The xed dose combination of candesartan/HCTZ has never been formally tested in this patient population, but the benets of blocking the RAS and enhancing diuresis are basic concepts in the treatment of HF. 51 HCTZ is recommended for the treatment of patients with HF in doses of 25 mg to initiate treatment and maintenance doses of between 2.5 and 100 mg daily. 51
Candesartan is recommended to be started at a dose of 4 or 8 mg daily and uptitrated to a target dose of 32 mg. The basis for the recommendation of candesartan was the results of the CHARM trial program. 52 In CHARM candesartan was tested in patients with systolic HF given either on top of an ACEi 53 or in cases of ACEi intolerance. 54
A third trial investigated the effect of candesartan in diastolic HF (HF with preserved systolic function). 55 Overall, 7601 patients were randomly assigned candesartan (titrated to 32 mg once daily) or matching placebo, and followed up for at least 2 years. In the overall CHARM trial program 82.8% of patients in the candesartan arm and 82.6% of patients in the placebo arm received diuretics and a further 16.9 and 16.6% respectively spironolactone. In CHARM Alternative (candesartan given instead of an ACEi) treatment resulted in a relative risk reduction (RRR) of death from cardiovascular cause or hospital admis- sion for worsening HF of 23% (ARR 7%, NNT 14, over 34 months of follow-up, adjusted P 0.0001 (Figure 6). 54
In the CHARM Added trial (candesartan on top of existing ACEi therapy) candesartan cotreatment resulted in a 15% RRR of cardiovascular death or hospital admission for CHF (ARR 4%, NNT 25, over 41 months of follow-up, adjusted P = 0.010). 54 The CHARM Preserved trial (candesartan in patients with HF but preserved systolic function) candesartan did not show a signicant reduction in the risk of the primary composite endpoint (adjudicated death from cardiovascular causes or admission with HF) but did show a signicant reduction in the number of patients admitted to hospital with CHF (ARR 3.3%, NNT 30, over 37 months follow up, P = 0.017). 55 In summary it appears possible to initiate drug treatment of HF with both combination agents at low dose, uptitrate Table 2 Laboratory values at baseline, and mean change (SD) from baseline a after 8 weeks of treatment 42
Candesartan 32 mg n = 653 Candesartan 32 mg 12.5 mg HCTZ n = 654 Candesartan 32 mg 25 mg HCTZ n = 664 S-urate (mol/L) Baseline 334.5 (84.6) 335.2 (82.6) 339.1 (80.6) Change 5.1 (52.0) 27.4 (52.3) 43.9 (57.8) S-potassium (mmol/L) Baseline 4.5 (0.4) 4.5 (0.4) 4.5 (0.4) Change 0.0 (0.4) 0.1 (0.4) -0.1 (0.4) S-glucose (mmol/L) Baseline 6.0 (1.4) 6.2 (1.9) 5.9 (1.5) Change 0.0 (1.0) 0.4 (1.0) 0.0 (0.9) S-triglycerides (mmol/l) Baseline 2.0 (1.4) 1.9 (1.8) 2.0 (1.5) Change 0.0 (1.2) 0.0 (1.6) 0.2 (2.2) S-cholesterol (mmol/L) Baseline 5.8 (1.1) 5.8 (1.1) 5.9 (1.0) Change 0.1 (0.7) 0.0 (0.8) 0.1 (0.8) S-creatinine (mol/L) Baseline 79.8 (15.8) 79.9 (14.8) 80.3 (15.4) Change 0.0 (10.5) 1.8 (9.8) 4.5 (13.1) a Baseline: after a run-in phase with 16 mg candesartan for 2 weeks and 32 mg candesartan for 6 weeks. Vascular Health and Risk Management 2009:5 1052 Mengden et al Dovepress submit your manuscript | www.dovepress.com Dovepress candesartan and HCTZ as warranted and, should the doses t, switch to a xed dose combination of candesartan 32/HCTZ 25 mg for maintenance treatment. Patients with stroke Stroke is a frequent, serious, and nally costly complication of hypertension. Candesartan was tested in 2 trials with respect to this indication, one testing the capability of preventing stroke or related disabilities (SCOPE, 56 see section Elderly patients), the other testing cerebro- and cardiovascular endpoints in patients with a history of stroke (ACCESS). 57 ACCESS was designed to evaluate the safety of early antihypertensive treatment in patients with acute cere- bral ischemia). 57 Patients with motor paresis and initial SBP 200 mmHg and/or DBP 110 mmHg or mean BP of 2 measurements 180 mmHg and/or 105 mmHg, respectively, were included. The trial was stopped prema- turely after the recruitment of 349 patients due to an imbal- ance in endpoints. Cumulative 12-month mortality and the number of vascular events differed signicantly in favor of the candesartan group (OR 0.475; 95% CI 0.2520.895). There were no cardiovascular or cerebrovascular events as a result of hypotension. Treatment was started with 4 mg candesartan daily on day 1. On day 2, dosage was increased to 8 or 16 mg candesartan if BP exceeded 160 mmHg systolic or 100 mmHg diastolic. In patients in the cande- sartan group who were still hypertensive on day 7 (mean daytime BP 135/85 mmHg), candesartan was increased or an additional antihypertensive drug (HCTZ, felodipine, metoprolol) was added. The control group received placebo for the rst 7 days and 8 to 16 mg candesartan throughout the rest of the study. In the ongoing SCAST trial (NCT00120003) candesartan is tested in patients with stroke (ischemic or hemorrhagic) and SBP 140 mmHg. Patients receive 4 mg candesartan on day 1; 8 mg on day 2; 16 mg on days 3 to 7. Dose adjust- ment in cases of SBP 120 mmHg, or symptomatic fall in BP are mandated. From day 8 therapies can be supplemented with any antihypertensive agent including diuretics. Taken together there is good evidence that early cande- sartan treatment after acute stroke might be able to prevent vascular events and mortality. The xed dose combination might be useful after several days of candesartan mono- therapy uptitration after which HCTZ in low dose is added to maintain or achieve BP control. Patients with diabetes mellitus Antihypertensive treatment in diabetic patients is complicated by the fact that baseline BP readings are usually high, while having to meet lower BP goals (130/80 mmHg in most cases). 17 ARBs are benecial within the context of diabetes because they have been shown to delay the development of diabetes more than any other drug class (Figure 7) 58,59 and to be at least neutral or even benecial with respect to metabolic parameters. As has been shown in a number of clinical trials, the reduction of cardiovascular morbidity following antihy- pertensive treatment is usually, but not always, pronounced in patients with diabetes. 60,61 Candesartan reduced the number of patients developing diabetes in the CHARM, 62 SCOPE, 63 and ALPINE trials. 64
When administered to a group of hypertensive subjects it p = 0.032 p < 0.0001 p < 0.0001 p = n.s. p = n.s. p = n.s. p = 0.010 p = n.s. All-cause mortality* Alternative Added Preserved Overall Hazard ratio 0.7 0.8 0.9 1.0 1.1 1.2 0.7 0.6 0.8 0.9 1.0 1.1 1.2 Hazard ratio Cardiovascular death or hospital admission for CHF
Figure 6 Results of the CHARM trial program.
5255 Notes: *p for heterogeneity 0.37;
p for heterogeneity 0.33.
Reprinted from Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. The Lancet. 362:759766. 52 Copyright 2003, with permission from Elsevier. Vascular Health and Risk Management 2009:5 1053 Candesartan cilexetil and HCTZ combination for hypertension Dovepress submit your manuscript | www.dovepress.com Dovepress reduced C-reactive protein and increased adiponectin and markers of insulin sensitivity, as measured by QUICKI (Quantitative Insulin-Sensitivity Check Index). 65 It also reduced BP effectively in diabetic patients. 66
Bramlage et al demonstrated in an observational study in primary care that candesartan 16/HCTZ 12.5 mg lowered BP effectively in patients with and without diabetes. 45 The absolute amount of BP lowering (27.2/13.4 mmHg) appeared to be dependent on baseline BP but did not differ among patient types (diabetes, metabolic syndrome, or neither condition). Microalbuminuria in diabetes is strongly predictive of nephropathy, end-stage renal disease, and premature cardiovascular morbidity and mortality. Effective preven- tive therapies are therefore a clinical priority. The effect of candesartan in the prevention of microalbuminuria was tested in a pooled analysis of the DIRECT trial program in which normotensive patients with type 1 (n = 3326) and 2 (n = 1905) diabetes were included. 67 Due to the study design the incidence of microalbuminuria was low in this analysis and no differences in the risk for albuminuria were noted (HR 0.95; 95% CI 0.781.16). Pooled results showed that the annual rate of change in albuminuria was 5.53% lower (CI, 0.73%10.14%; P = 0.024) with candesartan than with placebo. Studies conducted by Trenkwalder 68 and Mogensen 69
have however shown that candesartan is effective in lowering the level of albumin excretion in patients with hypertension, diabetes, and already existing microalbuminuria. Taking a much higher than recommended dose of the hypertension drug candesartan was shown to effectively lower the amount of protein excreted in the urine of patients with kidney disease in a study by Burgess et al. 70 269 patients with persistent proteinuria despite treatment with 16 mg candesartan were randomized to receive 16, 64, or 128 mg daily of candesartan for 30 weeks. It was found that patients taking 128 mg of candesartan experienced a 33% reduction in proteinuria compared with those receiving 16 mg candesartan by the end of the study. There is however a missing link between microalbuminuria reduction and morbidity and mortality endpoints which have so far been reported only from post-hoc analyses. A respective study is however already underway to provide this link. 71 Important in this respect are the results of the GUARD study that combined an ACEi with either amlodipine or HCTZ and demonstrated that with HCTZ the nephroprotective effect of benazepril was preserved while it was reduced when amlodipine was chosen as the combination partner. 72 The DIRECT trial program was a series of clinical trials investigating the effect of candesartan on the develop- ment and progression diabetic retinopathy who were either normotensive or had treated hypertension. 47,73 DIRECT consisted of three randomized, double-blind, placebo- controlled multicenter studies designed to investigate the potential for candesartan in halting the progression of, and possibly prevent, diabetic retinopathy. Results showed that candesartan was benecial for patients with type 2 diabetes who had established mild to moderate retinopathy, because candesartan had an additional, BP-independent effect on improvement of retinopathy (Figure 8). Candesartan was also shown to be indicated for patients with type 1 diabetes Treatment Odds ratio (95% CI of incident diabetes) ARBs ACE inhibitors Calcium-channel blockers blockers Diuretics 0.50 0.80 1.00 1.25 2.00 Favours treatment Favours placebo 0.822 (0.6790.999) 0.889 (0.7651.036) 1.051 (0.8931.263) 1.250 (1.0551.503) 1.347 (1.1331.632) Figure 7 Development of diabetes results of a meta-analysis. Reprinted from Lam SK, Owen A. Incident diabetes in clinical trials of antihypertensive drugs. The Lancet. 369:15131514. 59 Copyright 2007, with permission from Elsevier. Vascular Health and Risk Management 2009:5 1054 Mengden et al Dovepress submit your manuscript | www.dovepress.com Dovepress without retinopathy, in order to reduce their risk of developing retinopathy. In summary there is an abundance of evidence for the use of candesartan in patients with diabetes or a high risk for developing such. Data on the use of a xed dose combination of candesartan/HCTZ are scarce, leaving it unproven that a combination treatment is likewise benecial. Data addressing the dysmetabolic potential have however shown that the metabolic prole of HCTZ is neutralized when adding cande- sartan. Because of the need for multiple drugdrug combina- tions there is a clear need for combination therapy including diuretics, which are favored in common co-morbidities of diabetes, eg, CHF or diabetic nephropathy. Elderly patients The pharmacokinetics of candesartan were investigated after single and repeated once-daily doses in a trial by Hbner et al 74
of candesartan in the dose range 2 to 16 mg in both younger (1940 years) and elderly (6578 years) healthy volunteers. The area under the curve (AUC) and maximal concentration (C max ) of candesartan showed dose-proportional increases in the dose range of 2 to 16 mg candesartan after both single and repeated once-daily tablet intake, indicating linear pharma- cokinetics in both younger and elderly healthy subjects. The time to peak candesartan concentrations after tablet intake was consistently approximately 4 hour at all dose levels. Only mild AEs were recorded, with headache the most commonly reported event, and no increase in the number of reported AEs was observed with higher doses of candesartan cilexetil. 74 Results of the SCOPE study implied that candesartan treatment reduces cardiovascular morbidity and mortal- ity in old and very old patients with mild to moderate hypertension. 75,76 Candesartan-based antihypertensive treat- ment may also have positive effects on cognitive function and quality of life. SCOPE was a multi-center, prospective, randomized, double-blind, parallel-group study. The primary objective was to assess the effect of candesartan 816 mg once daily, on major cardiovascular events in elderly patients (7089 years of age) with mild hypertension (DBP 9099 and/or SBP 160179 mmHg). The main analysis showed that non-fatal stroke was reduced by 28% (P = 0.04) in the candesartan group compared with the control group, and there was a non-signicant 11% reduction in the primary endpoint, major cardiovascular events (P = 0.19). Signicant risk reduc- tions with candesartan in major cardiovascular events (32%, P = 0.013), cardiovascular mortality (29%, P = 0.049) and total mortality (27%, P = 0.018) were observed in patients who did not receive add-on therapy after randomization, and in whom the difference in BP was 4.7/2.6 mmHg. Other analyzes suggest positive effects of candesartan-based treat- ment on cognitive function, quality of life and new-onset dia- betes. Results of SCOPE strongly suggested that candesartan treatment reduces cardiovascular morbidity and mortality in old and very old patients with mild to moderate hypertension. Candesartan-based antihypertensive treatment may also have positive effects on cognitive function and quality of life. 76 Subgroup analyses from the CHARM study in patients with HF showed that older patients were at a greater absolute Changes in the ETDRS Scale at study end compared to baseline Candesartan Placebo P = 0.005 0 20 60 40 DIRECT-Prevent 1 80 P a t i e n t s
( % )
P a t i e n t s
( % )
P a t i e n t s
( % )
0 10 20 30 P = 0.03 DIRECT-Protect 1 5 4 3 2 1 1 2 3 4 5 0 0 10 20 30 P = 0.003 DIRECT-Protect 2 Figure 8 Results of the DIRECT trial program. 47,73 Vascular Health and Risk Management 2009:5 1055 Candesartan cilexetil and HCTZ combination for hypertension Dovepress submit your manuscript | www.dovepress.com Dovepress risk of adverse CV mortality and morbidity outcomes, but derived a similar RRR and, therefore, a greater absolute benet from treatment with candesartan, despite receiving a somewhat lower mean daily dose of candesartan. 77
Adverse effects were more common with candesartan than with placebo, although the relative risk of adverse effects was similar across age groups. The benet to risk ratio for candesartan was thus favorable across all age groups. In summary, given that diuretics are frequently indicated in elderly patients there appears to be a role for xed dose combinations of candesartan/HCTZ. But again evidence has been acquired with free combinations of candesartan with other antihypertensive drugs including thiazide diuretics. Economic evaluation The addition of candesartan to standard therapy for CHF pro- vided important clinical benets at little or no additional cost in France, Germany, and the UK, according to a detailed eco- nomic analysis focusing on major cardiovascular events and prospectively collected resource-use data from the CHARM- Added and CHARM-Alternative trials in patients with CHF and left ventricular (LV) systolic dysfunction. 78 Results of a corresponding cost-effectiveness analysis showed that can- desartan was either dominant over placebo or was associated with small incremental costs per life-year gained, depending on the country and whether individual trial or pooled data were used. Preliminary data from a US cost-effectiveness analysis based on CHARM data also showed favorable results for candesartan cilexetil. Two cost-effectiveness analyses of candesartan cilexetil in hypertension have been published, both conducted in Sweden. Data from the SCOPE trial in elderly patients with hypertension, which showed a significant reduction in non-fatal stroke with candesartan-based therapy versus non-candesartan based treatment, were incorporated into a Markov model and an incremental cost-effectiveness ratio of 12,824 per QALY gained was calculated (2001 value). In conclusion, despite some inherent limitations, economic analyses incorporating CHARM data and conducted primarily in Europe have shown that candesartan cilexetil appears to be cost-effective when added to standard CHF treatment in patients with CHF and compromised LV systolic function. The use of candesartan cilexetil as part of antihypertensive therapy in elderly patients with elevated BP was also deemed to be cost effective in a Swedish analysis, primarily resulting from a reduced risk of non-fatal stroke (as shown in the SCOPE study); however, the generalizability of results to other contexts has not been established. Cost-effectiveness analyses comparing candesartan cilexetil with ACE inhibitors or other angiotensin receptor blockers in CHF or hypertension are lacking, and results reported for candesartan cilexetil in a Swedish economic analysis of ALPINE data focusing on outcomes for diabetes require conrmation and extension. Conclusions The xed dose combination of candesartan and HCTZ is a valuable addition to the armamentarium of drugs in the treatment of hypertension, because of its high efcacy in reducing BP, its tolerability, and the high compliance of patients with treatment. Comparative studies with losartan/ HCTZ have consistently shown a higher clinical efcacy with the candesartan/HCTZ combination. Candesartan/HCTZ therefore assists both physicians and patients in achieving long-term treatment goals. Data on the reduction of cardiovascular endpoints with fixed dose combinations of antihypertensive drugs are scarce, as are the data for candesartan/HCTZ. However many trials have tested candesartan versus a non-RAS blocking comparator based on a standard therapy including thiazide diuretics. The indications tested were HF and stroke, and particular emphasis was put on elderly patients or those with diabetes. In patients with HF, for example, the xed dose combination might be applied in patients in whom indi- vidual titration resulted in a dose of 32 mg candesartan and 25 mg HCTZ which can then be combined into one tablet to increase compliance with treatment. Also in patients with stroke the xed dose combination might be used in patients in whom maintenance therapy with both components is considered. Abbreviations ACCESS, The Acute Candesartan Cilexetil Therapy in Stroke Survivors; ACCOMPLISH, Avoiding Cardiovas- cular Events in Combination Therapy in Patients Living with Systolic Hypertension; ACEi, ACE inhibitor; AE, adverse event; ALPINE, Antihypertensive treatment and Lipid Prole In a North of Sweden Efcacy Evaluation; ARB, angiotensin receptor blocker; ARR, absolute risk reduction; AT, angiotensin; AUC, area under the curve; BP, blood pressure; CANDIA, CANdesartan and DIuretic vs Amlodipine in hypertensive patients; CCB, calcium channel blocker; CHARM, Candesartan in Heart Failure- Assessment of Reduction in mortality and Morbidity; CHD, coronary heart disease; CHF, chronic heart failure; CI, condence interval; CV, cardiovascular; DBP, diastolic blood pressure; DDD, dened daily doses; DIRECT, The Vascular Health and Risk Management 2009:5 1056 Mengden et al Dovepress submit your manuscript | www.dovepress.com Dovepress DIabetic REtinopathy Candesartan Trials; DRC, drug regimen compliance; ESC, European Society of Cardiol- ogy; ESH, European Society of Hypertension; HCTZ, hydrochlorothiazide; HDL, high-density lipoprotein; HF, heart failure; HR, hazard ratio; JNC, Joint National Com- mittee; LIFE, Losartan Intervention For Endpoint reduction in hypertension; LV, left ventricular; MOSES, Morbidity and Mortality after Stroke Eprosartan vs Nitrendipine for Secondary Prevention; NHS, National Health Service (UK); NICE, National Institutes of Clinical Excellence; NNT, num- ber needed to treat; OR, odds ratio; QUICKI, Quantitative Insulin-Sensitivity Check Index; PRA, plasma renin activity; QALY, quality adjusted life year; RAS, reninangiotensin system; RRR, relative risk reduction; SBP, diastolic blood pressure; SCAST, Scandinavian Candesartan Acute Stroke Trial; SCOPE, Study on COgnition and Prognosis in the Elderly; UK, United Kingdom; US, United States. 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A Comparison of The Efficacy and Safety of irbesartan/HCTZ Combination Therapy With Irbesartan and HCTZ Monotherapy in The Treatment of Moderate Hypertension