Impact of Nicorandil on Renal Function in Patients With Acute Heart Failure and Pre-Existing Renal Dysfunction Masahito Shigekiyo, Kenji Harada, Ayumi Okada, Naho Terada, Hiroyoshi Yoshikawa, Akira Hirono, Takashi Yamamoto, Hirofumi Yamamoto, Katsuya Tamura, Hiroyuki Fujinaga Tokushima Prefectural Central Hospital, Department of Cardiology, Tokushima, Japan Disclosure Information : No conflict of interest
Background (1) Acute heart failure (AHF) management and outcome have not changed over the past decade. Recent guidelines for the treatment of AHF have recommended pharmacotherapy with vasodilators as preferable to inotropic agents in patients without excessively low blood pressure. Renal dysfunction is often present and/or worsens in patients with AHF and is an important prognostic factor for AHF. The beneficial effects of vasodilators for renal function in AHF remain to be clearly shown.
Background (2) Nicorandil is vasodilator that has nitrate-like properties and activates ATP-sensitive potassium channels and results in balanced venous and arterial vasodilation. (Taira N et al. Am J Cardiol 1989;63:18J-24J) N O N H ONO2 Nitrate-like action Reduce preload by dilating vein K ATP channel opener Reduce afterload by dilating arteries CH2-ONO2 CH-ONO2 CH2-ONO2 Nitroglycerin
(mmhg) 30 A bolus intravenous administration of nicorandil improves immediately PCWP and CI in patients with AHFS PCWP Intravenous administration of nicorandil (0.2mg/kg) over 5min (L/min/m 2 ) 4 3.5 Cardiac Index * * 25 20 * 3 2.5 15 10 * ** 2 PCWP reduced by 30% CI increased by 15% 1.5 0 5 15 30 60 0 5 15 30 60 Time after administration (min) Time after administration (min) *: p<0.05, **: p<0.01 (vs Baseline), Mean±S.E. Kato K et al. Jpn Pharmacol Ther 2008;36:S25-S34
Background (3) Ischemia or hypoxia of organs is common in patients with AHF. Nicorandil can protect various organs, such as heart and kidney, from ischemia-reperfusion-induced damage via activation of mitochondrial K ATP channels, like ischemic preconditioning. Nicorandil dilates afferent arterioles by opening K ATP channels, and thereby increases renal blood flow.
Object To evaluate the impact of nicorandil on renal function in patients with AHF and pre-existing renal dysfunction.
Data sources We presented a randomized, controlled trial in AHF patients in ESC congress 2011. Subjects were assigned to receive standard therapy (Control group) or nicorandil in addition to standard therapy (NCR group). Of those patients, 91 had renal dysfunction on admission and they were enrolled in this study.
Inclusion and Exclusion Criteria Inclusion criteria: Renal dysfunction on admission (egfr<60 ml/min/1.73m 2 ) Over 20 years of age Major exclusion criteria: Hypotension at baseline (SBP < 90mmHg) Significant lung disease that could interfere with interpretation of dyspnea Acute coronary syndrome Severe renal and/or hepatic dysfunction
Study protocol Admission/ Baseline Enrolment/ Initial treatment (O 2,diuretics,NTG) <1hr from admission Before Control group (n=48) (standard therapy ) NCR group (n=43) (Nicorandil in addition to standard therapy ) 24hrs RX 24h Nicorandil ; 0.2mg/kg bolus, followed by continuous infusion of 0.2mg/kg/hr for 24 hours Standard therapy; All patients received intravenous administration of carperitide (hanp) which was administered with a initial dose of 0.0125μg/kg/min.
Measurements Systolic and diastolic blood pressure Echocardiographic findings Renal parameter (egfr and BUN)
Baseline Characteristics (1) Control group (n=48) NCR group (n=43) P value Age (yrs) 75.6±10.7 75.9±12.7 0.92 Male gender 27 (56.3) 18 (41.9) 0.17 BMI (kg/m 2 ) 23.0±4.6 22.7±4.1 0.70 Medical history Heart failure readmission 21 (43.8) 14 (32.6) 0.27 Hypertension 35 (72.9) 33 (76.7) 0.68 Dyslipidemia 14 (29.2) 12 (27.9) 0.89 Diabetes 20 (41.7) 18 (41.9) 0.99 Myocardial infarction 8 (16.7) 10 (23.3) 0.43 Atrial fibrillation or flutter 14 (29.2) 15 (34.9) 0.56 Values are numbers (%) or mean±sd.
Baseline Characteristics (2) Physical findings and symptoms Control group (n=48) NCR group (n=43) P value SBP on admission (mmhg) 148.0±2 152.8±3 0.38 DBP on admission (mmhg) 85.6±1 87.2±2 0.65 HR on admission (bpm) 96.9±2 101.2±2 0.28 NYHA class (II/ III/ IV) 1/ 9/ 38 3/ 6/ 34 0.46 Echocardiography LVEF < 40% 18 (37.5) 18 (43.9) 0.54 Laboratory findings BNP (pg/ml) 887 (401-1608) 1015 (679-1443) 0.49 egfr (ml/min/1.73m 2 ) 35.1±15.0 32.9±14.1 0.47 BUN (mg/dl) 30.3±17.8 36.5±17.8 0.10 Values are numbers (%), mean±sd. and median (IQR)
Baseline Characteristics (3) Oral medication on admission Control group (n=48) NCR group (n=43) P value ACE-I/ ARBs 29 (60.4) 24 (55.8) 0.66 Beta blockers 17 (35.4) 17 (39.5) 0.69 Statins 15 (31.3) 10 (23.3) 0.39 Loop diuretics 24 (50.0) 23 (53.5) 0.74 IV medication during the first 24 hours Carperitide 48 (100.0) 43 (100.0) 1.00 Dose (μg/kg/min) 0.020 (0.014-0.029) 0.025 (0.017-0.031) 0.05 Loop diuretics 37 (77.1) 33 (76.7) 0.97 Dobutamine 2 (4.2) 1 (2.3) 1.00 Dopamine 2 (4.2) 3 (7.0) 0.66 Values are numbers (%).
Blood pressure (mmhg) Changes in blood pressure over time Systolic BP Diastolic BP
Echocardiographic parameters at baseline and 1h after treatment Control group NCR group Baseline 1h p value Baseline 1h p value E (cm/s) 104.0±35.3 98.2±32.2 0.073 110.1±37.7 92.6±27.8 0.004 Ea (cm/s) 4.7±2.2 4.4±1.9 0.099 4.2±1.9 4.8±1.7 0.014 E/Ea ratio 28.1±19.2 27.3±16.9 0.725 31.6±17.6 21.3±8.9 <0.001 DcT (cm) 149.3±45.2 159.5±52.6 0.141 141.4±54.4 181.6±63.8 0.002 IVC (mm) 20.5±4.4 19.8±3.7 0.198 19.8±4.7 17.6±4.2 0.002 E, early transmitral diastolic velocity; Ea, early diastolic mitral annular tissue Doppler; DcT, deceleration time of E velocity; IVC, inferior vena cava
Changes in echocardiographic parameters at 1h after treatment Control group NCR group E (cm/s) Ea (cm/s) E/Ea ratio DcT (cm) IVC (mm) -6.7 0.6-0.8 38.8-0.6-0.3 10.2-17.5-10.4-2.3 p=0.099 p=0.003 p=0.007 p=0.030 p=0.034
Changes in renal parameter from admission to discharge Percent changes in renal parameter (%) (%) Incidence of worsening of renal parameter p=0.037 p=0.001 p=0.001 p=0.001 %egfr Control group %BUN NCR group egfr -25% BUN 25% Any parameter
60-day all-cause mortality or rehospitalization of heart failure (%) p=0.28 HR=0.55 (0.17-1.60) 20.0% 11.6% 60-day Death / HF 60-day follow-up rate was 97% (88/91)
Summary Nicorandil could be safely administered to patients with AHFS and pre-existing renal dysfunction in the urgent phase without excessively low BP. Administration of nicorandil to standard therapy prevented worsening of renal function and improved echocardiographic findings (E, E/Ea, DcT ) rapidly in patients with AHFS.
Conclusion These findings suggest that Nicorandil prevent worsening of renal dysfunction and improve LV function in patients with AHFS and pre-existing renal dysfunction.