A BISOPROLOL hatékonysága krónikus szivelégtelenségben (CIBIS II, III tanulmányok eredményei) Prof. Dr. Kikeli Pál István

CIBIS II Következtetések A CIBIS II tanulmány bizonyitja, hogy a Bisoprolol mint szelektiv ß1-receptor blokkoló a standard ACE gátló és diurétikum terápiához társitva – szignifikánsan csökkenti az össz mortalitást, valamint a kórházi beutalások számát krónikus szivelégtelenségben A Bisoprolol az első olyan ß-blokkoló amelyik hatékonynak bizonyult egy olyan tanulmányban melynek elsődleges végpontja az összhalálozás volt. A Bisoprololt szedő és a placebo csoportban a kezelést abbahagyók aránya egyaránt 15% volt. In conclusion, when given in addition to standard therapy with diuretics and ACE inhibitors, beta-blockade with bisoprolol significantly reduces all-cause mortality and all-cause hospitalisation in patients with CHF. Bisoprolol is the first beta-blocker to have proven its efficacy in a single large-scale CHF study with all-cause mortality as the primary objective. Bisoprolol was as well tolerated as placebo with a permanent treatment withdrawal rate of 15% in both groups. As a result of CIBIS II and other large mortality studies on beta-blockade in CHF (MERIT-HF and COPERNICUS) the latest European guidelines (1) clearly state that bisoprolol, metoprolol or carvedilol are now recommended for the treatment of all patients with stable, mild, moderate and severe heart failure and reduced left ventricular ejection fraction. Furthermore, they stipulate that, unless contra-indicated, all patients in NYHA classes II to IV should receive a beta-blocker as first-line therapy, in addition to standard treatment. 1. Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22(17):1527-60 2. CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13

CIBIS II Survival 34% reduction in all-cause mortality with bisoprolol 1.0 0.8 Bisoprolol: 156 deaths (n = 1327) Placebo: 228 deaths (n = 1320) log rank test, p < 0.0001 Survival At the second interim analysis, the study was stopped on the advice of the Advisory and Safety Committee, because a significant difference in total mortality of p<0.0001 had been observed. Patients were therefore followed up for a mean of 1.3 years. In the bisoprolol group, 156 (11.8%) patients died, compared with 228 (17.3%) in the placebo group (p<0.0001), amounting to a mortality reduction of 34%. The estimated annual mortality rate was 8.8% in the bisoprolol group and 13.2% in the placebo group. The magnitude of the mortality reduction seen in CIBIS II is consistent with meta-analyses of previous randomized placebo-controlled trials, and with the subsequent MERIT-HF study on metoprolol (1) (34% reduction in mortality) and the COPERNICUS study on carvedilol (2) (35% reduction in mortality). 1. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-9 2. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344(22):1651-8 3. CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 0.6 200 400 600 800 Time after inclusion (days) 34% reduction in all-cause mortality with bisoprolol

CIBIS II Causes of deaths Patients 100 p=0.0011 80 83 6% Bisoprolol (n = 1327) 60 Placebo (n = 1320) p=0.0012 p=0.17 49 4% There were significantly fewer cardiovascular deaths among patients on bisoprolol than among those on placebo (p=0.0049). Sudden death (within one hour of symptoms without previous worsening of heart failure symptoms) was reduced by 44% (p=0.0011), and there were non-significantly fewer deaths related to pump failure. The strikingly lower frequency of sudden deaths among patients receiving bisoprolol in CIBIS II suggests an important antiarrhythmic effect. Rates of deaths classified as due to MI, other cardiovascular causes or non-cardiovascular causes were not statistically significantly different between groups, although numbers were small. Strikingly, however, there was a significant reduction in deaths due to unknown causes (23 in the bisoprolol group compared with 49 in the placebo group, p=0.0012), and it has to be assumed that many of these deaths were in fact from cardiovascular causes. Due to the strict definitions in CIBIS II for sudden deaths or those associated with pump failure, many deaths had, therefore, to be classified as being of unknown cause. Unwitnessed or insufficiently documented deaths classified as unknown were probably sudden and some associated with pump failure. CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 48 4% 47 4% CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 40 p=0.58 36 3% 28 2% p=0.41 20 23 2% 23 2% p=0.75 18 1% 14 1% 7 1% 8 1% Sudden Pump Myocardial Other cardio- Non-cardio- Unknown cause death failure infarction vascular deaths vascular deaths of death Hazard ratio: (95% CI) 0.56 0.74 0.85 1.17 0.75 0.45 (0.39 – 0.80) (0.48 – 1.14) (0.31 – 2.34) (0.67 – 2.03) (0.37 – 1.50) (0.27 – 0.74)

CIBIS III következtetése 60-65 éves egyéneknél NYHA II-III as szivelégtelenségben 35% os ejekciós frakció mellett a bisoprolollal kezdett kezelés számottevően csökkentette a hirtelen halál gyakoriságát az enalaprillal kezdett kezelési csoporttal szemben

Sudden death – entire study 10 Bisoprolol-first vs enalapril-first: 29 versus 34 sudden deaths; HR 0.84; 95% CI 0.51-1.38; P=0.487 8 6 Enalapril-first Bisoprolol-first 4 2 Time (months) 6 12 18 N at risk 505 467 373 125 505 473 384 116

CIBIS II Dózis titrálása Bisoprolol adag (mg) 10.00 7.50 5.00 The study drugs were up-titrated gradually according to tolerability. Patients were started on bisoprolol 1.25 mg (n= 1327) or placebo (n=1320) daily, the drug being increased successively to 2.50 mg, 3.75 mg, 5.00 mg, 7.50 mg, and 10.00 mg, according to tolerance. Patients received the first three concentrations of each dose for 1 week, and the higher concentrations for 4 weeks. Investigators were asked to ensure that the highest tolerated dose was reached and maintained, if possible, for the duration of the trial. In contrast to earlier trials on carvedilol, there was no run-in period, and the assessment of clinical efficacy was not thereby confused by the exclusion of patients intolerant to the beta-blocker. The most common dose of bisoprolol during the maintenance phase was 10.0 mg (reached in 564 patients); 152 reached 7.5 mg and 176 reached 5.0 mg. CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 3.75 2.50 1.25 W1 W2 W3 W4 W5 W6 W7 W8 W9 W10 W11 W12 W13 W14 W15 W16 hetek Dózis titrálás az egyéni tolerancia függvényében

CIBIS II: Dose-response relationship Methods Bisoprolol tertile groups*: n=565 43% 10 mg/day High dose n=328 24% 5 mg/day 7.5 mg/day Moderate dose n=434 33% 1.25 mg/day 2.5 mg/day 3.75 mg/day Low dose Simon T et al. on behalf of CIBIS II investigators. Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study (CIBIS II). Eur Heart J 2003; 24: 552-559 The data of the total CIBIS II patient population (bisoprolol n=1327, placebo n=1320) were allocated to three tertile groups: low-moderate-high dose. Simon T et al. on behalf of CIBIS II investigators. Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study (CIBIS II). Eur Heart J 2003; 24: 552-559 *according to the last tolerated dose before an event or at last follow-up visit

A mortalitás és morbiditás csökkenése dózisfüggő CIBIS II: A mortalitás és morbiditás csökkenése dózisfüggő Szignifikáns mortalitás csökkenés érhető el A Bisoprolol kis-közepes-illetve nagy adagjával placebohoz viszonyitva A Bisoprolol nagy (p=0.0001) illetve közepes (p=0.001) adagjaival az a kis adagokhoz viszonyitva A kardiovaszkuláris halálozás és a kórházi beutalások aránya kisebb a nagy-illetve közepes Bisoprolol adagot szedő csoport esetében a kis adagot szedő csoporthoz viszonyitva Simon T et al. on behalf of CIBIS II investigators. Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study (CIBIS II). Eur Heart J 2003; 24: 552-559 To summarise: bisoprolol treatment produced a significant survival benefit regardless of dose. However, the mortality seen in the high and moderate dose groups was significantly lower than in the low dose group. The same applied to the risk of cardiovascular death, all-cause hospitalisation and cardiovascular hospitalisation. Simon T et al. on behalf of CIBIS II investigators. Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study (CIBIS II). Eur Heart J 2003; 24: 552-559

Jobb alacsony adagot adni, mint egyáltalán nem adni! CIBIS II: Következtetések Szignifikáns túlélés javulást lehet elérni a Bisoprolol minden adagjával Tartsuk a Bisoprolol adagot a beteg által tolerált maximális szinten, igyekezzünk a céldózis elérésére A Bisoprolol kezelés abbahagyása esetén szignifikáns mortalitás növekedés észlelhető ezért igyekezzünk a kezelést folyamatosan fenntartani amennyiben a beteg tolerálja Simon T et al. on behalf of CIBIS II investigators. Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study (CIBIS II). Eur Heart J 2003; 24: 552-559 Since mortality was reduced at all dose levels, it is clearly important to continue bisoprolol treatment at the patient’s highest tolerated dose, even if the dose is low. In addition, any discontinuation of bisoprolol treatment increases the risk of mortality further – it is vital therefore that treatment is continued wherever possible. Simon T et al. on behalf of CIBIS II investigators. Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study (CIBIS II). Eur Heart J 2003; 24: 552-559 Jobb alacsony adagot adni, mint egyáltalán nem adni!