CANOCORD 16MG Tablet

Pharmacotherapeutic group: Angiotensin II antagonists, plain, ATC code: C09CA06 Mechanism of action Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays an important role in the pathophysiology of hypertension, heart failure, and other cardiovascular diseases.‍‍‍‍‍‍​​​‍​​​​​​ It also plays a significant role in the pathogenesis of organ hypertrophy and other organ damage. The principal physiological effects of angiotensin II (e.g., vasoconstriction, stimulation of aldosterone secretion, regulation of water and mineral homeostasis, and stimulation of cell growth) are mediated through stimulation of the type 1 (AT1) receptor. Pharmacodynamic effects Candesartan cilexetil is an inactive prodrug suitable for oral administration. Upon administration, candesartan cilexetil is rapidly converted during absorption from the gastrointestinal tract by ester hydrolysis to the pharmacologically active metabolite, candesartan. Candesartan is an AIIRA selective for AT1 receptors, with tight binding to and slow dissociation from the receptor. It has no agonistic activity. Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and degrades bradykinin. It does not affect ACE and does not increase concentrations of bradykinin or substance P. In controlled clinical trials comparing candesartan with ACE inhibitors, the incidence of cough was lower in the candesartan cilexetil-treated group. Candesartan does not bind to or block other receptors or other effector sites important in cardiovascular regulatory mechanisms. Antagonism of angiotensin II (AT1) receptors produces a dose-dependent increase in plasma concentrations of renin, angiotensin I and II, and a decrease in plasma aldosterone concentrations. Clinical efficacy and safety Hypertension In patients with hypertension, candesartan causes a dose-dependent, long-lasting reduction in arterial blood pressure. The antihypertensive effect is due to a decrease in systemic peripheral resistance, without reflex increase in heart rate. There is no evidence of severe first-dose hypotension or rebound phenomenon after discontinuation of treatment. After a single dose of candesartan cilexetil, onset of antihypertensive effect occurs within 2 hours. With repeated dosing, the maximum antihypertensive effect, regardless of dose, is generally achieved within 4 weeks, and the antihypertensive effect is sustained. Results of a meta-analysis showed that the average additional effect of increasing the dose from 16 mg to 32 mg once daily was small. Taking into account interindividual variability, a greater than average effect can be expected in some patients. Once-daily administration of candesartan cilexetil provides an effective and smooth blood pressure reduction over 24 hours, with small differences between peak and trough blood pressure values measured between doses. The antihypertensive effect and tolerability of candesartan and losartan were compared in two randomised, double-blind trials in 1,268 patients with mild to moderate hypertension. The trough blood pressure reduction (systolic/diastolic) was 13.1/10.5 mmHg for candesartan cilexetil 32 mg once daily and 10.0/8.7 mmHg for losartan potassium 100 mg once daily (difference in blood pressure reduction 3.1/1.8 mmHg, p<0.0001/p<0.0001). The combination of candesartan cilexetil with hydrochlorothiazide has an additive effect on blood pressure reduction. An enhanced antihypertensive effect is also observed when candesartan cilexetil is combined with amlodipine or felodipine. Candesartan is equally effective in all patients regardless of age or sex. Medicinal products that block the renin-angiotensin-aldosterone system have a less pronounced antihypertensive effect in Black patients compared to other patients (typically a "low-renin" population). This also applies to candesartan. In an open-label clinical trial involving 5,156 patients with diastolic hypertension, blood pressure reduction during candesartan treatment was significantly lower in Black patients than in other patients (14.4/10.3 mmHg versus 19.0/12.7 mmHg, p<0.0001/p<0.0001). Candesartan increases renal blood flow and maintains or increases glomerular filtration rate (GFR), while renal vascular resistance and filtration fraction are reduced. In a three-month clinical trial in hypertensive patients with type 2 diabetes mellitus and microalbuminuria, antihypertensive treatment with candesartan cilexetil reduced urinary albumin excretion (albumin/creatinine ratio by an average of 30%, 95% CI 15–42%). Currently, no data are available on the effect of candesartan on progression of diabetic nephropathy. In a randomised clinical trial in 4,937 elderly patients (age 70–89, of whom 21% were aged 80 and older) with mild to moderate hypertension followed for a mean of 3.7 years, the effect of candesartan cilexetil administered once daily at a dose of 8–16 mg (mean 12 mg) on cardiovascular morbidity and mortality was investigated (SCOPE – Study on Cognition and Prognosis in the Elderly). Patients received candesartan cilexetil or placebo together with other antihypertensive therapy added as needed. In the candesartan group, blood pressure fell from 166/90 to 145/80 mmHg, and in the control group from 167/90 to 149/82 mmHg. For the primary endpoints, major cardiovascular events (cardiovascular mortality, non-fatal stroke and non-fatal myocardial infarction), no statistically significant differences were found. There were 26.7 events per 1,000 patient-years in the candesartan-treated group compared with 30 events per 1,000 patient-years in the control group (relative risk 0.89, 95% CI 0.75 to 1.06, p = 0.19). Paediatric population – hypertension The antihypertensive effects of candesartan were evaluated in hypertensive children aged 1 to <6 years and 6 to <17 years in two randomised, double-blind, multicentre, 4-week dose-ranging studies. In children aged 1 to <6 years, 93 patients were randomised, 74% of whom had renal disease, to receive candesartan cilexetil oral suspension at doses of 0.05, 0.20 or 0.40 mg/kg once daily. The primary analysis method was the slope of the change in systolic blood pressure (SBP) as a function of dose. SBP and diastolic blood pressure (DBP) decreased by 6.0/5.2 to 12.0/11.1 mmHg from baseline across the three candesartan cilexetil dosing regimens. However, since no placebo group was included, the true magnitude of blood pressure effect remains unclear, making a definitive assessment of the benefit-risk balance difficult for this age group. In children aged 6 to <17 years, 240 patients were randomised in a ratio of 1:2:2:2 to receive placebo or low, medium, and high doses of candesartan cilexetil. For children weighing <50 kg, candesartan cilexetil doses were 2, 8, or 16 mg once daily. For children weighing >50 kg, candesartan cilexetil doses were 4, 16, or 32 mg once daily. Candesartan at pooled doses reduced systolic BP by 10.2 mmHg (P < 0.0001) and diastolic BP by 6.6 mmHg (P = 0.0029) from baseline. In the placebo group, systolic BP also decreased by 3.7 mmHg (p = 0.0074) and diastolic BP by 1.80 mmHg (p = 0.0992) from baseline. Despite the substantial placebo effect, all individual candesartan doses (and all pooled doses) were significantly superior to placebo. Maximum blood pressure lowering response was achieved at 8 mg in children weighing less than 50 kg and at 16 mg in children weighing more than 50 kg, with the effect plateauing at this point. 47% of study respondents were Black patients and 29% were female; the mean age ± SD was 12.9 ± 2.6 years. In children aged 6 to <17 years, a tendency towards a lesser blood pressure effect was observed in Black patients compared with patients of other races. Heart failure As demonstrated in the CHARM programme – Candesartan in Heart failure – Assessment of Reduction in Mortality and morbidity, treatment with candesartan cilexetil reduces mortality, reduces hospitalisation for heart failure, and improves symptoms in patients with left ventricular systolic dysfunction. This placebo-controlled, double-blind study programme in patients with chronic heart failure (CHF) with NYHA functional class II–IV consisted of three separate studies: CHARM-Alternative (n = 2,028) in patients with LVEF ≤ 40% not treated with an ACE inhibitor due to intolerance (mainly due to cough, 72%), CHARM-Added (n = 2,548) in patients with LVEF ≤ 40% treated with an ACE inhibitor, and CHARM-Preserved (n = 3,023) in patients with LVEF > 40%. Patients on optimal background therapy were randomised to placebo or candesartan cilexetil (at a dose titrated from 4 mg or 8 mg once daily to 32 mg once daily, or the highest tolerated dose, with a mean dose of 24 mg), with a median follow-up of 37.7 months. After six months of treatment, 63.3% of patients taking candesartan cilexetil (89%) were on the target dose of 32 mg. In the CHARM-Alternative study, the composite endpoint of cardiovascular mortality or first hospitalisation for chronic heart failure was significantly reduced with candesartan compared with placebo, hazard ratio (HR) 0.77 (95% CI: 0.67 to 0.89, p < 0.001), corresponding to a 23% relative risk reduction. This endpoint occurred in 33% of candesartan patients (95% CI: 30.1 to 36.0) and 40.0% of placebo patients (95% CI: 37.0 to 43.1), an absolute difference of 7.0% (95% CI: 11.2 to 2.8). Fourteen patients required treatment during the study; one patient to prevent cardiovascular death, the remainder were hospitalised for heart failure treatment. The composite endpoint of all-cause mortality or first hospitalisation for chronic heart failure was also significantly reduced with candesartan, HR 0.80 (95% CI: 0.70 to 0.92, p = 0.001). This endpoint occurred in 36.6% of candesartan-treated patients (95% CI: 33.7 to 39.7) and 42.7% of placebo-treated patients (95% CI: 39.6 to 45.8), an absolute difference of 6.0% (95% CI: 10.3 to 1.8). Both mortality and morbidity (hospitalisation for chronic heart failure), as components of these composite endpoints, contributed to the favourable effects of candesartan. Treatment with candesartan cilexetil led to improvement in NYHA classification (p = 0.008). In the CHARM-Added study, the composite endpoint of cardiovascular mortality or first hospitalisation for chronic heart failure was significantly reduced with candesartan compared with placebo, HR 0.85 (95% CI: 0.75 to 0.96, p = 0.011), corresponding to a 15% relative risk reduction. This endpoint occurred in 37.9% (95% CI: 35.2 to 40.6) of candesartan-treated patients and 42.3% (95% CI: 39.6 to 45.1) of placebo-treated patients, an absolute difference of 4.4% (95% CI: 8.2 to 0.6). Twenty-three patients required treatment during the study; one patient to prevent cardiovascular death, the remainder were hospitalised for heart failure treatment. The composite endpoint of all-cause mortality or first hospitalisation for chronic heart failure was also significantly reduced with candesartan, HR 0.87 (95% CI: 0.78 to 0.98, p = 0.021). This endpoint occurred in 42.2% of candesartan-treated patients (95% CI: 39.5 to 45.0) and 46.1% of placebo-treated patients (95% CI: 43.4 to 48.9), an absolute difference of 3.9% (95% CI: 7.8 to 0.1). Both mortality and morbidity as components of these composite endpoints contributed to the favourable effects of candesartan. Treatment with candesartan cilexetil led to improvement in NYHA classification (p = 0.020). In the CHARM-Preserved study, no statistically significant reduction was achieved in the composite endpoint of cardiovascular mortality or first hospitalisation for chronic heart failure, HR 0.89 (95% CI: 0.77–1.03, p = 0.118). All-cause mortality was not statistically significant when assessed separately in each of the three CHARM studies. However, all-cause mortality was also assessed in the pooled population: CHARM-Alternative and CHARM-Added, HR 0.88 (95% CI: 0.79 to 0.98, p = 0.018), and across all three studies, HR 0.91 (95% CI: 0.83 to 1.00, p = 0.055). The beneficial effect of candesartan was similar regardless of age, sex, and concomitant medication. Candesartan was also effective in patients concomitantly receiving beta-blockers and ACE inhibitors, and the beneficial effect was achieved regardless of whether patients were or were not taking ACE inhibitors at target doses recommended by treatment guidelines. In patients with chronic heart failure and reduced left ventricular systolic function (LVEF ≤ 40%), candesartan reduces systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and angiotensin II concentrations, and reduces aldosterone levels. Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) evaluated the use of a combination of an ACE inhibitor with an angiotensin II receptor blocker. The ONTARGET study was conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes mellitus with evidence of end-organ damage. The VA NEPHRON-D study was conducted in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies showed no significantly beneficial effect on renal and/or cardiovascular outcomes and mortality, whereas an increased risk of hyperkalaemia, acute kidney injury and/or hypotension was observed compared with monotherapy. Given the similar pharmacodynamic properties, these results are also relevant for other ACE inhibitors and angiotensin II receptor blockers. ACE inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy. The ALTITUDE study (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was designed to evaluate the benefit of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular death and stroke were numerically more frequent in the aliskiren group than in the placebo group, and adverse events and serious adverse events of interest (hyperkalaemia, hypotension, and renal dysfunction) were more frequently reported in the aliskiren group compared with the placebo group.