• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
Nuevas perspectivas en el tratamiento de la angina crónica estable - Dr. Juan Tamargo Menéndez
 

Nuevas perspectivas en el tratamiento de la angina crónica estable - Dr. Juan Tamargo Menéndez

on

  • 1,974 views

Nuevas perspectivas en el tratamiento de la angina crónica estable.

Nuevas perspectivas en el tratamiento de la angina crónica estable.
Congreso de las Enfermedades Cardiovasculares 2009.
22/10/2009 Barcelona
Sociedad Española de Cardiología

Statistics

Views

Total Views
1,974
Views on SlideShare
1,920
Embed Views
54

Actions

Likes
3
Downloads
0
Comments
1

4 Embeds 54

http://www.secardiologia.es 24
http://profesionales.secardiologia.es 19
http://www.slideshare.net 10
http://translate.googleusercontent.com 1

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel

11 of 1 previous next

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
  • Very good presentation
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • The I f current drives the diastolic depolarization slope, thereby increasing or decreasing the slope. Therefore, it becomes clear, looking at this diagram, that any drug able to increase the intensity of the I f current would increase the diastolic depolarization slope, and that any drugs able to inhibit the I f current would slow the diastolic depolarization slope. So, the I f current drives the diastolic depolarization slope, the frequency of action potentials, and thus the heart rate.
  • Analysis of the safety and tolerability from the three major trials of the short-term use of ranolazine – at doses ranging from 500 mg bid to 1000 mg bid – confirmed that the incidence of adverse events was dose-related and that the most common adverse events were constipation and dizziness.

Nuevas perspectivas en el tratamiento de la angina crónica estable - Dr. Juan Tamargo Menéndez Nuevas perspectivas en el tratamiento de la angina crónica estable - Dr. Juan Tamargo Menéndez Presentation Transcript

  • Nu evas perspectivas en el tratamiento de la angin a crónica estable Juan Tamargo Departamento de Farmacología, Facultad de Medicina Universidad Complutense, Madrid. Spain
  • A ngina crónica estable
    • La CI es la principal causa de muerte en Europa (740,000 muertes/año)
    • La angina crónica estable es la manifestación más común en casi el 70% de los pacientes
      • 20,000–40,000/millón de habitantes en la UE
      • Incidencia y prevalencia aumentan:
        • Envejecimiento de la población, aumento de arteriosclerosis, mayor supervivencia post-IM
      • Reduce la capacidad funcional, la QoL y la supervivencia
      • Importante repercusión económica (EU 49 billones € /año )
    Fox K et al. Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J. 2006;27:1341-81.
  • A ngina crónica estable
    • Muchos pacientes persisten sintomáticos y en riesgo a pesar de un tratamiento médico agresivo y de revascularizaciones 1
      • Al cabo de 1 año ~ 10–25% de los pacientes siguen con la angina y un 60–80% requiere tratamiento médico 2
    (1) Gibbons RJ et al. J Am Coll Cardiol. 2003;41:159-168. (2) Scirica and Morrow. Curr Cardiol Rep 2007; 9: 272-278
    • Necesitamos nuevos fármacos con mecanismos de acción distintos pero complementarios
    • En pacientes con patología asociada (HTA, DM, IC, bradicardia) puede ser difícil alcanzar las dosis adecuadas
      • Hipotensión, bradicardia, BAV, depresión contráctil
    8 5 7 8 18 61 58 0 10 20 30 40 50 60 70 Comorbid conditions (%) Myocardial infarction Peripheral vascular disease Respiratory disease Diabetes Hypertension Hyperlipidaemia Signs of heart failure
  • New mechanistic approaches to myocardial ischemia Sinus node inhibition (IVABRADINE) Late I Na inhibition (Ranolazine) Rho kinase inhibition (fasudil) Metabolic modulation (trimetazidine) Preconditioning (nicorandil) O H 3 C O H 3 C O N CH 3 O CH 3 O CH 3 O O NO 2 H N N N N O N CH 3 H CH 3 CH 3 O O H N SO 2 NH N O OH CH 3 CH 3 OCH 3 H N N N O
  • Papel de la frecuencia cardiaca
    • Aporte/
    • demanda de O 2
     Frecuencia Cardiaca  Trabajo cardiaco  Demanda de O 2  Duración diástole  Perfusión coronaria  Aporte de O 2 MVO 2 Frecuencia Contractilidad
    • Tensión parietal:
    • Precarga
    • Poscarga
  • -50 -50 50 0 mV -50 -50 pA I f I f I CaT I CaL I K Potenciales de acción registrados en el nodo SA (A) y en miocitos ventriculares (B) PU PDM
    • Se une de forma específica al canal HCN y bloquea la corriente I f
    • Aplana la fase 4 y reduce la frecuencia cardiaca
    -60 mV 0 mV  RR Na + K + Na + Ivabradina 0 1 s Mecanismo de acción de ivabradina
  • Cardiopatía Isquémica Inhibir la  -oxidación de los ácidos grasos, aumentar la oxidación de la glucosa Trimetazidina Oxfenicina Etoxomir Perhexilina S-15176
  • Corriente tardía de entrada de Na (I NaL ) 1. 2.
    • Su papel en condiciones fisiológicas
    • Situaciones en las que aumenta esta corriente
    • Papel de la I NaL en el miocardio isquémico – un nuevo paradigma
    • Ranolazina: un nuevo fármaco antianginoso y antiisquémico que inhibe la I NaL
  • Cardiac Na + channels Tamargo and Mugelli, 2009 Na +
    • Phase 0
    • Excitability
    • Cond. Velocity
    • QRS
    85 mV Peak I Na
  • Coraboeuf et al. Am J Physiol 1979;236:H561-H567 “ They shortening was due to a TTX-sensitive Na + current flowing during the plateau of the action potential” “ This current flows through a small proportion of Na+ channels with no inactivation mechanism (or inactivation different from normal), e.g. the late I na Tetrodotoxin prolongs the APD in Purkinje fibers at concentrations lower than those at which it inhibited the I Na 1: control. 2: TTX (0.03  M) Late I Na
  • Late Na current in guinea pig ventricular myocytes Kiyosue and Arita. Circ Res 1989;64:389-97 Late Peak 0 Late Peak 0
    • Late I Na
    • Slowly inactivating
    • Late reopenings
    • Bursting behaviou r
    • Two types of Na + channel activity: brief openings (PEAK) and sustained openings with rapid interruptions (burst type) (LATE)
    • Channels that either do not close, or close and then reopen
  • Gating modes in cardiac Na + channels (Nav1.5  subunit) expressed in HEK cells Late I Na results from two types of channel activity: scattered late openings and burst openings Undrovinas et al. J Mol Cell Cardiol 2002; 34:1477-1489
  • Pathological and pharmacological conditions associated with an increase in late I Na Pathological Conditions:
    • 3. Pharmacological
    • Toxins: ATX-II, AP-A,  -PMTX, Pyrethroids
    • Drugs (Na + channel modulators):
    • DPI 201–106, BDF 9148
    • Second messengers (CaM, CaMKII  )
    • 4. Inhibitors of late I Na
    • Sodium channel blockers: Mexiteline, Lidocaine, Flecainide
    • Toxins: Tetrodotoxin, Saxitoxin
    • Acquired
    • Hypoxia
    • Ischemic metabolites (amphiphiles)
    • Oxygen free radicals
    • Thrombin
    • Angiotensin II
    • Heart failure
    • Post-MI remodeling
    • LV hypertrophy
    • Mutations in ion channel/accessory protein of Na + channels
    • Gain-of-function mutations ( Δ KPQ)
    Ranolazine
  • Ischemic conditions are associated with an increase in late I Na Lysophosphatidylcholine Control
    • Acquired
    • Hypoxia
    • Reactive oxygen species (ROS)
    • Ischemic metabolites
    • Thrombin
    • Angiotensin II
    • Heart failure
    • Post-MI remodeling
    • LV hypertrophy
  • Murphy E. et al. Physiology 2008;23:115-123 2008 Representative changes in Na, Ca, Mg, ATP, PCr, and pH during ischemia
  • A pathological paradigm NaCh inactivation failure Ischemia Ca 2+ Overload  late I Na  Na + i NCX
  • Diastolic relaxation failure increases O 2 consumption and reduces O 2 supply
    • Na + and Ca 2+ overload Increased wall tension during diastole:
      • Increases MVO 2
      • Compresses intramural small vessels
      • Reduces myocardial blood flow (subendocardium)
    • Worsens ischemia and angina
  • Consequences of late Na + current dysfunction
    • Diseases (eg, ischemia, heart failure)
    • Pathological milieu (reactive O 2 species, ischemic metabolites)
    • Toxins and drugs (eg, ATX-II, etc.)
    Na + channel (Gating mechanism malfunction)
    • Increase ATP
    • consumption
    • Decrease ATP formation
    Oxygen supply and demand
    • Abnormal contraction and relaxation
    •  diastolic tension (  LV wall stiffness)
    Mechanical dysfunction
    • Early after potentials
    • Beat-to-beat Δ APD
    • Arrhythmias (VT)
    Electrical instability Belardinelli et al. Eur Heart. 6 (Suppl. I):13-17, 2004
  • Transmural heterogeneity of late I Na Late I Na is more prominent in M and Purkinje cells Zygmunt et al. Am J Physiol 2001;281:H689-H697 Pathological Iate I Na increases the dispersion of ventricular repolarization, may trigger early afterdepolarizations and lead to reentrant excitation Endo M cell Epi ECG
  • Consequences of increasing the late I Na Leading to QT prolon ga tion, EADs and beat-to-beat variation in APD Song et al. J Cardiovasc Pharmacol 2004; Maltsev et al. Eur J Heart Fail 2007 Human failing heart Cardiac myocytes exposed to ATX-II
  • Abnormal Late I Na Prolongs APD (QTc), induced EADs and delayed relaxation Na + in out Na + Channel Na v 1.5 Sodium Current Action Potential 0 Late I Na 0 (Upstroke) 1 2 (Plateau) 3 4 Peak Normal 0 Late I Na Peak Abnormal Q S T Q S T Twitch Phasic Phasic Tonic EAD DAD
  • Late I Na is involved in the Long QTS * Andersen—Tawil Syndrome ** Timothy Syndrome 1505-1507  Late I Na SNTA1,  -1 Syntrophin LQT12  I Ks AKAP9, Yotiao LQT11  Late I Na SCN4B, NavB4 LQT10  Late I Na CAV3, Caveolin-3 LQT9  I Ca CACNA1C, Ca v 1.2 LQT8**  I K1 KCNJ2, Kir2.1 LQT7*  I Kr KCN2, MiRP1 LQT6  I Ks KCNE1, minK LQT5  Ca i ,  Late I Na ? KCNH2, HERG LQT4  Late I Na KCNQ1, KvLQT1 LQT3  I Kr KCNH2, HERG LQT2  I Ks KCNQ1, KvLQT1 LQT1 Channel Gene 50 ms 5 pA Normal 50 ms Enhanced (  KPQ) I NaL I NaL
  • Positive feedback during ischaemia increases the imbalance between myocardial O 2 supply and demand Ca 2+ overload Ischemia  O 2 supply/  MVO 2  Late I Na  [Na + ] i
    • extravascular compression
    • (  O 2 supply)
    Contracture (  LVEDP) Deleterious Positive Feedback Cycle X
  • Ranolazine selectively inhibits the late I Na Late I Na Peak I Na abnormal Ranolazine Control Δ IC 50 = 38-fold A. Ventricular Myocytes from Canine Failing Hearts 50 0 100 % Inhibition Peak IC 50 = 244 µM late IC 50 = 6.5 µM 1E-3 0.01 0.1 1 10 100 Concentration of Ranolazine (mM) Rajamani S., et al., Eur Heart J 207;28: 400 (abstract) ACE que no se controla con otros antianginosos, o en pacientes que no pueden tomar estos medicamentos. O OH CH 3 CH 3 OCH 3 H N N N O
  • Ranolazine: mechanism of action Hasenfuss G, Maier LS. Clin Res Cardiol 2008;97:222-26 Maier LS. Cardiol Clin 2008;26:603-14. Ischemia ↑ Late I Na Na + overload Ca ++ overload Mechanical dysfunction ↑ Diastolic tension ↓ Contractility Electrical dysfunction Arrhythmias O2 supply & demand ↑ ATP consumption ↓ ATP formation NCX NCX: sodium-calcium exchanger Ranolazine
  • Ranolazine reduces Na + and Ca 2+ overload induced by ATX-II in rabbit myocytes Sossalla S et al. J Mol Cell Cardiol 2008; 45: 32-43. 0 10 20 30 * End-diastolic pressure (mmHg) 40 * P<0.05 Control Ranolazine Na + overload Diastolic [Ca 2+ ] i
  • Ranolazine reduces the increase in diastolic tension in LV trabeculae from human failing heart Sossalla S et al.. J Mol Cell Cardiol 2008; 45: 32-43.
  • Ranolazine: Key Clinical Trials ROLE N=746 Chronic angina Chaitman BR, et al. JAMA. 2004;291:309-316. Stone PH, et al. J Am Coll Cardiol. 2006;48:566-575. Morrow DA, et al. JAMA. 2007;297:1775-1783. J Am Coll Cardiol 2004;43:1375– 82 CARISA N=823 Chronic angina Ranolazine vs placebo on top of standard therapy ERICA N=565 Chronic angina Ranolazine vs placebo on top of amlodipine 10mg MERLIN TIMI-36 N=6560 Non-STE ACS Ranolazine vs placebo on top of standard care MARISA N=191 Chronic angina Ranolazine vs placebo Total patients enrolled = 8,139
  • CARISA Efficacy Change from baseline (sec) Peak Trough *** ** ** *** ** * * * * * 50 100 150 Exercise duration Time to angina Time to 1-mm ST-depression Exercise duration Time to angina Time to 1-mm ST-depression Placebo Ranolazine 750 mg b.i.d. Ranolazine 1,000 mg b.i.d. n = 791, ITT/LOCF; LS means ± SE. *p<0.05; **p  0.01 ***p  0.001 vs placebo ITT: Intent To Treat LOCF: Last Observation Carried Forward Chaitman BR, et al. JAMA 2004;291:309-16.
  • MERLIN TIMI-36 trial CV Death, MI, or Recurrent Ischaemia (% at 12 months) 0 10 20 30 0 180 360 540 Days from randomisation HR 0.92 (95% CI 0.83 to 1.02) P=0.11 Ranolazine 21.8% (n=3,279) Placebo 23.5% (n=3,281) Recurrent Ischemia (%) Days from Randomization Ranolazine 17.3% (N=3,279) Placebo 20.0% (N=3,281) HR 0.87 (95% CI 0.76 to 0.99) P =0.030 0.00 0.05 0.10 0.15 0.20 0.25 0 180 360 540 Percentage (%) p=0.048 p=0.005 p=0.002 8.1 16.4 21.1 5.6 12.5 16.5 0 5 10 15 20 25 Worsening Angina New anti- anginal therapy Reccurrent Ischemia Placebo n = 1,776) Ranolazine n = 1,789)
  • Rate of tachyarrhythmias detected on cECG monitoring after Non-ST-segment MI Scirica et al. Circulation 2007;116:1647-1652.
  • Scirica et al. Circulation 2007 Morrow, D. A. et al. Circulation 2009 Cahnege in HbA1c and estimated risk of recurrent ischemia at 1 year in patients allocated to ranolazine vs placebo stratified by diabetes status 0.48% reduction (P = 0.008 Ranolazine 750 mg bid vs placebo
  • Short-term safety and tolerability 8 (2.8) 7 (2.5) 2 (1.1) 1 (0.6) 4 (2.2) 6 (2.2) 7 (2.5) 4 (1.5) Headache N/A N/A 2 (1.1) 0 4 (2.2) 6 (2.2) 4 (1.4) 5 (1.9) Fatigue 6 (2.1) 3 (1.1) 1 (0.6) 0 0 9 (3.3) 1 (0.4) 1 (0.4) Asthenia 8 (2.8) 2 (0.7) 2 (1.1) 1 (0.6) 1 (0.6) 15 (5.5) 10 (3.6) 2 (0.7) Nausea 11 (3.9) 7 (2.5) 8 (4.4) 2 (1.1) 1 (0.6) 19 (6.9) 10 (3.6) 5 (1.9) Dizziness 25 (8.9) 5 (1.8) 4 (2.2) 0 0 20 (7.3) 17 (6.1) 2 (0.7) Constipation 112 (39.9) 100 (35.3) 41 (22.8) 29 (16.0) 27 (15.1) 90 (32.7) 87 (31.2) 71 (26.4) Any AE Treatment-emergent adverse events (AE) reported in ≥2% of patients and more frequently on ranolazine than on placebo No modifica los intervales RR, PR, QRS or QTc* 1,000 mg n=281 Placebo n=283 1,000 mg n=180 500 mg n=181 Placebo n=179 1,000 mg n=275 750 mg n=279 Placebo n=269 ERICA Trial bid for 6 wks MARISA Trial bid dosing 1 week CARISA Trial bid for 12 weeks
  • A new and complementary mechanism Na + -induced Ca 2+ overload Ischemia O 2 demand O 2 supply
    • Mechanical dysfunction
    • Electrical instability
    • Decreased ATP formation
    Ranolazine Nitrates Beta-blockers CaCBs Heart rate Contractility Preload Afterload Coronary supply  MVO 2
    • La I NaL juega un importante papel en el acúmulo de Na + y Ca 2+ en el miocardio isquémico
    • Contribuye a la disfunción mecánica, eléctrica y metabólica
    • Representa una nueva diana terapéutica
    • La Ranolazina es un inhibidor selectivo de la I NaL que disminuye el acúmulo de Na + y de Ca 2+ inducido por la isquemia
    • NO modifica la frecuencia cardiaca, la conducción AV o la PA
    • Este mecanismo es distinto, pero complementario con el de los antianginosos clásicos
    • Tratamiento sintomático de a angina crónica estable que no se controlan adecuadamente o no toleran los antianginosos convencionales
    Conclusiones