Newer anti anginals

Newer anti anginals Dr Julian Johny ThottianINTRODUCTION Chronic angina is a condition that impairs quality of life and is associated with decreased life expectancyCardiac metabolism- LCFAs are the major source of energy (80%) and Glucose (20%) in aerobic conditions.In fetus , the main source of energy is glucose and shift to FFA is in the early post natal period.

Cardiac metabolism

Current therapies that reduce angina frequency and increase the threshold at which demand-induced myocardial ischemic symptoms become evident include : Drugs :Nitrates, -blockers, Calcium antagonist Exercise conditioning Enhanced External Counterpulsation Coronary revascularizationCurrent antianginal strategiesCurrent anti-anginal strategiesNon pharmacologicPharmacologicTrimetazidineFasudilNicorandilIvabradineRanolazineExercise trainingEECPChelationtherapySCSTMR5The three main nonpharmacologic antianginal techniques currently under evaluation are enhanced external counterpulsation, transmyocardial revascularization, and spinal cord stimulation. They are generally reserved for refractory angina.EECP uses three paired pneumatic cuffs that are applied to the lower extremities. The cuffs are sequentially inflated then deflated.TMR involves the creation of channels in the myocardium with a laser. SCS uses an implanted device with an electrode tip that extends into the dorsal epidural space, usually at the C7-T1 level.1Their mechanisms of action are not completely understood and a number of hypotheses have been proposed.Current nonpharmacologic antianginal strategiesGibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina: A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for the Management of Patients with Chronic Stable Angina). 2002. Available at www.acc.org/clinical/guidelines/stable/ stable.pdf.

Consequences associated with dysfunction of late sodium current

Diseases(eg, ischemia, heart failure)

Pathological milieu(reactive O2 species,ischemic metabolites)

Toxins and drugs(eg, ATX-II, etc.)Na+ channel

(Gating mechanism malfunction)Increase ATP consumptionDecrease ATP formation

Oxygen supply and demand Abnormal contraction and relaxation diastolic tension(LV wall stiffness)

Mechanicaldysfunction Early after potentials Beat-to-beat APD Arrhythmias (VT)

Electricalinstability8Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497 ( Pt 2):337-347.Undrovinas AI, Fleidervish IA, Makielski JC. Inward sodium current at resting potentials in single cardiac myocytes induced by the ischemic metabolite lysophosphatidylcholine. Circ Res. 1992;71:1231-1241.Wu J, Corr PB. Palmitoyl carnitine modifies sodium currents and induces transient inward current in ventricular myocytes. Am J Physiol. 1994;266:H1034-H1046.Ward CA, Giles WR. Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. J Physiol. 1997;500 ( Pt 3):631-642.Huang B, El Sherif T, Gidh-Jain M, Qin D, el Sherif N. Alterations of sodium channel kinetics and gene expression in the postinfarction remodeled myocardium. J Cardiovasc Electrophysiol. 2001;12:218-225.Murphy E, Perlman M, London RE, Steenbergen C. Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ Res. 1991;68:1250-1258.Jansen MA, van Emous JG, Nederhoff MG, van Echteld CJ. Assessment of myocardial viability by intracellular 23Na magnetic resonance imaging. Circulation. 2004;110:3457-3464.Diastolic relaxation failure increases oxygen consumption and reduces oxygen supplyIncreased myocardial tension during diastole:Increases myocardial O2 consumptionCompresses intramural small vesselsReduces myocardial blood flow Worsens ischemia and angina

9Cellular calcium overload causes impaired contractility and, more significantly, impaired relaxation. Sustained contraction of the ischemic cardiomyocyte during diastole, or diastolic relaxation failure, consumes energy.This increases the demand for oxygen and worsens ischemia and angina.Sustained contraction of the ischemic cardiomyocyte during diastole, or diastolic relaxation failure, also causes compression of the intramural vessels that supply the myocardium with blood and oxygen.This significantly reduces myocardial blood flow and oxygen supply, since most blood flow to the heart occurs during diastole.As a consequence, ischemia and angina become worse.

Meyer M, Keweloh B, Guth K, Holmes J, Pieske B, Lehnart S, Just H, Hasenfuss G. Frequency-dependence of myocardial energetics in failing human myocardium as quantified by a new method for the measurement of oxygen consumption in muscle strip preparations. J Mol Cell Cardiol. 1998;30:1459-1470.Zile MR, Baicu CF, Gaasch WH. Diastolic heart failureabnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004;350:1953-1999.

Advances Ischemic heart disease is a prevalent clinical conditionImproved understanding of ischemia has prompted new therapeutic approachesRho kinase inhibitionMetabolic modulationPreconditioningInhibition of If and late INa currents10Ischemic heart disease and associated symptoms continue to present a major public health challenge.A number of new therapeutic approaches are under investigation, includingRho kinase inhibitionMetabolic modulationPreconditioning via K+ channel activationInhibition of If and late INa currentsTwo of these approaches (late INa inhibition and inhibition of fatty acid oxidation) reduce angina with minimal or no pathophysiologic effects. Thus, they are potentially complementary to traditional medications (beta-blockers, calcium channel blockers, and nitrates).

SummaryRanolazine (N-(2,6-dimethyphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide) is a substituted piperazine compound.pFOX inhibitor -that ranolazine only inhibits fatty-acid oxidation during the periods of elevated plasma FFA levels associated with myocardial ischaemiaLate sodium current blocker

Understanding Angina at the Cellular LevelIschemia impairs cardiomyocyte sodium channel functionImpaired sodium channel function leads to:Pathologic increased late sodium currentSodium overloadSodium-induced calcium overloadCalcium overload causes diastolic relaxation failure, which:Increases myocardial oxygen consumptionReduces myocardial blood flow and oxygen supplyWorsens ischemia and angina

RanolazineIschemia Late INaNa+ OverloadDiastolic relaxation failureExtravascular compressionCa++ OverloadChaitman BR. Circulation. 2006;113:2462-247212Ischemia is associated with disruptions in cellular sodium and calcium homeostasis.

An enhanced late sodium current is likely to contribute to the sodium overload observed in ischemia. Late phase sodium channels have been shown to remain open longer in ischemic conditions. Sodium overload may result from decreased efflux and increased influx during ischemia, with greater intracellular accumulation of sodium as the duration of ischemia increases.

This is followed by an increase in intracellular Calcium through the Na/Ca exchanger on the myocyte wall.

Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497 ( Pt 2):337-347. Murphy E, Perlman M, London RE, Steenbergen C. Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ Res. 1991;68:1250-1258.Jansen MA, van Emous JG, Nederhoff MG, van Echteld CJ. Assessment of myocardial viability by intracellular 23Na magnetic resonance imaging. Circulation. 2004;110:3457-3464.Na+/Ca2+ overload and ischemiaAdapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13. Late Na+ current Diastolic wall tension (stiffness)Intramural small vessel compression( O2 supply) O2 demandNa+ overloadCa2+ overloadMyocardial ischemia13It is proposed that Na+-related Ca2+ overload mediates a vicious cycle of ischemia begetting more ischemia.Ca2+ overload may result in increased left ventricular diastolic tension. As a result, myocardial O2 consumption increases and intramural small vessels are compressed, causing increased O2 demand and decreased O2 supply, respectively.Positive feedback during ischemia increases the imbalance between myocardial oxygen supply and demand.

Na+/Ca2+ overload and ischemiaSodiumCurrent0Late

Peak

0

LatePeakSodiumCurrent

Na+

ImpairedInactivationNa+IschemiaMyocardial ischemia causes enhanced late INaAdapted from Belardinelli L et al. Eur Heart J Suppl. 2006;(8 suppl A):A10-13.Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.14Na+ influx is controlled by a number of channels. The current flowing through voltage-gated Na+ channels is responsible for the upstroke of the action potential.Activation of these channels permits Na+ entry, with inactivation occurring a few milliseconds after. The channels remain closed and nonconducting throughout the plateau phase of the action potential. However, a small proportion of channels either do not close or close and then reopen. These channels allow a sustained current of Na+ to enter. This current is referred to as the late Na+ current to distinguish it from the peak current.Emerging data indicate that a number of pathologic diseases or conditions may be associated with a prolongation of the late Na+ current. Among these pathologic diseases is myocardial ischemia.Accumulation of Na+ secondary to enhanced late INa leads to activation of the reverse mode of the Na+/Ca2+ exchanger, with subsequent efflux of excess Na+ and influx of Ca2+. Eventually, Ca2+ overload of the cell results.

Myocardial ischemia causes enhanced late INa

Ranolazine hemodynamic affects No affect of Blood Pressure or Heart RateCan be added to Conventional Medical therapy, especially when BP and HR do not allow further increase in dose of BetaBlockers, Ca Channel blockers, and Long Acting Nitrates.Ranolazine has twin pronged action.pFOXLate Na inward entry blockadeMetabolic modulation (pFOX) and ranolazineClinical trials showed ranolazine SR 5001000 mg bid (~26 mol/L) reduced anginaExperimental studies demonstrated that ranolazine 100 mol/L achieved only 12% pFOX inhibitionRanolazine does not inhibit pFOX substantially at clinically relevant doses Fatty acid oxidation Inhibition is not a major antianginal mechanism for ranolazineMacInnes A et al. Circ Res. 2003;93:e26-32.Antzelevitch C et al. J Cardiovasc Pharmacol Therapeut. 2004;9(suppl 1):S65-83.Antzelevitch C et al. Circulation. 2004;110:904-10.pFOX = partial fatty acid oxidation17MacInnnes et al reported experimental data demonstrating that ranolazine partially inhibits fatty acid oxidation in a dose-dependent manner. At a concentration of 100 mol/L, they observed 12% inhibition of oxidation.This concentration is substantially greater than the concentration achieved in humans at currently recommended doses (~26mol/L).Thus, inhibition of fatty acid oxidation is not a major antianginal mechanism for ranolazine. An alternative mechanism has been proposed and will be discussed in later slides.Metabolic modulation (pFOX) and ranolazineMedication ClassImpact on HRImpact on BPPhysiologic MechanismBeta BlockersDecrease pump functionCalc Channel BlockersDecrease Pump function + Vaso-dilitationNitratesVaso-dilitationRanolazineOOReduced Cardiac StiffnessPharmacologic Classes for Treatment of AnginaMyocardial ischemia: Sites of action of anti-ischemic medication

Consequences of ischemiaCa2+ overloadElectrical instabilityMyocardial dysfunction(systolic function/ diastolic stiffness)

Ischemia O2 DemandHeart rateBlood pressurePreloadContractility O2 Supply

Development of ischemiaTraditionalanti-ischemicmedications:-blockersNitratesCa2+ blockersCourtesy of PH Stone, MD and BR Chaitman, MD. 2006.Ranolazine19Ranolazine, in contrast to older antianginal medications, appears to work downstream of the ischemic insult, complementing traditional medications mechanism of action.Myocardial ischemia: Sites of action of anti-ischemic medication3 ranolazine trials

20Baseline characterstics

NO MUCH BENEFIT IN ACS

Contraindications Ranolazine is known to increase the QT interval on the electrocardiogram. Mean increase in the corrected QT interval (QTc) is approximately 6 msec, about 5% of individuals may have QTc prolongations of 15 msec or longer. (MARISA)

It blocks Ikr and hence prolongs the QT interval.Clinical experience in coronary syndrome population did not show an increased risk of proarrhythmia or sudden deathStrong CYP3A4 inhibitors and drug that interact with P glycoprotein

ContdUsed with caution with other CYP3A4 inhibitors and also drugs that prolong QT.INTERACTS withDigoxin , simvastatin ,cyclosporine, diltiazem, verapamil, ketoconazole, macrolides , grape fruit juice

Other beneficial effectsUS FDA has granted permission for- HbA1c reduction incoronary artery diseasepatients withdiabetesand antiarrhythmic benefits according to the results of MERLIN TIMI 36 trial. Uses in heart failure and neuropathic pain are being studied extensively.

Side effectsThe most common adverse events that led to discontinuation placebo were Dizziness (1.3% versus 0.1%) Nausea (1% versus 0%) Asthenia, Constipation Headache (each about 0.5% versus 0%). Doses above 1000 mg twice daily are poorly tolerated.

Conclusions from CARISA MARISA & ERICASinus node inhibition: IvabradineDiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.IVABRADINESA nodeAV nodeCommon bundleBundle branchesPurkinje fibers

30Ivabradine selectively targets the Na+/K+ current (If current) in pacemaker cells of the sinoatrial node.Channels that carry the If current are unique to the sinoatrial node, although ion channels in the retina have a similar structure and are probably the source of mild, transient visual disturbances in some patients taking If blockers.1Sinus node inhibition: IvabradineTardif J-C, Ford I, Tendera M, Bourassa MG, Fox K, for the INITIATIVE Investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529-2536.Sinus node inhibition: IvabradineIf current is an inward Na+/K+ current that activates pacemaker cells of the SA nodeIvabradineSelectively blocks If in a current-dependent fashionReduces slope of depolarization, slowing HRDiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.402002040600.5Potential (mV)ControlIvabradine 0.3 MTime (seconds)31Ivabradine selectively targets the Na+/K+ current (If current) in pacemaker cells of the sinoatrial node.Channels that carry the If current are unique to the sinoatrial node, although ion channels in the retina have a similar structure and are probably the source of mild, transient visual disturbances in some patients taking If blockers.1Sinus node inhibition: IvabradineTardif J-C, Ford I, Tendera M, Bourassa MG, Fox K, for the INITIATIVE Investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529-2536.Trials associatedIt produces similar effects to those of atenolol, as measured in the randomized double-blind INITIATIVE trial, which compared ivabradine (5, 7.5 and 10 mg bid) with atenolol at doses of 50 and 100 mg per day and found to be non inferior.It is safe agent and no changes in QT interval.ASSOCIATE Trial is double blind RCT done on 889 patients which found that ivabradine was better than placebo in anti anginal and anti ischaemic efficacy. Combination of this drug and betablockers was definitely effective without untoward effects.

BEAUTifUL TRIAL-post hoc analysisThe BEAUTIFUL investigators sought to analyze, post hoc, the effect of ivabradine on patients with limiting angina at baseline within the BEAUTIFUL trial. Patients with limiting angina -13.8% of the trial population. 24% reduction in the primary endpoint [cardiovascular mortality or hospitalization for fatal and non-fatal myocardial infarction (MI) or heart failure HR, 0.76; 95% CI, 0.581.00] and a 42% reduction in hospitalization for MI (HR, 0.58; 95% CI, 0.370.92). In patients with heart rate 70 bpm, there was a 73% reduction in hospitalization for MI (HR, 0.27; 95% CI, 0.110.66) and a 59% reduction in coronary revascularization (HR, 0.41; 95% CI, 0.170.99). These results indicate that ivabradine is most helpful to reduce adverse cardiac events in patients with limiting angina and that in this population, its benefit may extend well beyond symptom control. Side effect /effectsBlurring of vision No QT prolongationNo negative inotropic propertiesImprovements in exercise tolerance and prevention of exercise-induced ischaemiaMetabolic modulation (pFOX): TrimetazidineO2 requirement of glucose pathway is lower than FFA pathwayDuring ischemia, oxidized FFA levels rise, blunting the glucose pathwayFFAGlucoseAcyl-CoAAcetyl-CoAPyruvateEnergy for contractionMyocytes-oxidationTrimetazidineMacInnes A et al. Circ Res. 2003;93:e26-32.Lopaschuk GD et al. Circ Res. 2003;93:e33-7.Stanley WC. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S31-45.pFOX = partial fatty acid oxidationFFA = free fatty acid35The free fatty acid oxidation hypothesis arose out of advances in understanding of myocardial metabolic pathways.Myocardial cells derive their energy via fatty acid and glucose metabolism. During ischemia the fatty acid pathway predominates. However, this pathway requires more oxygen than the glucose pathway.1Theoretically, inhibition of fatty acid oxidation should promote a shift towards the more oxygen-efficient glucose pathway.Lopaschuk et al and Stanley have reported experimental data showing that the antianginal trimetazidine is an inhibitor of partial fatty acid oxidation (pFOX). However, MacInnes et al did not observe any inhibition with trimetazidine in other experimental models.Thus, inhibition of fatty acid oxidation as a major antianginal mechanism for trimetazidine remains to be definitively established.Metabolic modulation (pFOX): TrimetazidineChaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, et al, for the MARISA Investigators. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43:1375-1382.It is piperazine derivative (1-[2,3,4-trimethoxibenzyl)]-piperazine). Launched as a cytoprotective agent.No significant negative inotropic or vasodilator properties either at rest or during dynamic exerciseTRIMPOL II RCT of 426 patients with CSA who were randomised to either trimetazidine 20 mg three times a day or placebo in addition to metoprolol 50mg. This study demonstrated an improvement in time to STsegment depression on exercise tolerance testing (ETT), total exercise workload, mean nitrate consumption, and angina frequency in patients randomised to receive trimetazidine

Large multicentric trial of 19000 patients post MI by EMIP-FR group showed no benefit of iv infusion of trimetazidine immediately post MI over 48hrs MOA CPT -1 inhibitor and also acts in inhibition of the enzyme long-chain 3-ketoacyl coenzyme A thiolase (LC 3- KAT)[Kantor et al]VASCO ,largest RCT , showed no benefit as an add on in anginaSafety issues and adverse effects ?????Side effects Extrapyramidal and parkinsonian symptoms recently published by EMA 2012Restless leg syndrome.Use is limited in severe renal impairment.Perhexilene Earlier designed as a CCB but doesnot act like a CCBIt doesnot affect the heart rate or SVRMultiple randomised trials show that it has anti anginal effect as monotherapy or as combination.Inhibition of CPT-1 and, to a lesser extent, CPT-2, resulting in increased glucose and lactate utilisationS/E hepatotoxicity and peripheral neuropathy due to phospholipid accumulation as a result of CPT inhibition.Cole et al confirmed the safety of perhexiline in a randomised, double-blind, crossover study following initiation of 100 mg of perhexiline BD with subsequent plasma-guided dose titration; none of the developed the dreaded side effects.Other s/e nausea ,dizziness and hypoglycaemiaOther uses symptomatic aortic stenosis

Circulation 1990;81(4):126070

Etomoxir/ OxfenicinePotential anti anginal agentLaunched as an anti diabetic agent due to hypoglycaemic effectsCPT 1 INHIBITORImprovement in LV function in rats- Turcani & RuppSingle study available on humans (15 patients) with NYHA II III Etomoxir 80mg was administered.\Only animal studies on oxfenicine.

Preconditioning: NicorandilNitrate-associated effectsVasodilation of coronary epicardial arteriesActivation of ATP-sensitive K+ channelsIschemic preconditioningDilation of coronary resistance arteriolesIONA Study Group. Lancet. 2002;359:1269-75.Rahman N et al. AAPS J. 2004;6:e34.NOONO2HN42Nicorandil possesses a nitrate moiety and, therefore, produces hemodynamic effects similar to those of long-acting nitrates.It activates cyclic GMP (cGMP), dilates capacitance vessels, and decreases preload.Nicorandil is also capable of opening ATP-sensitive K+ (KATP) channels. These channels are involved in dilation of coronary resistance arterioles, which decreases afterload, and are also thought to mimic ischemic preconditioning, a potential cardioprotective effect.Preconditioning: NicorandilDOSAGE- 20mg bidTolerance is seen with chronic dosageNo cross tolerance with nitratesThe Impact Of Nicorandil in Angina (IONA) trial showed a significant reduction of major coronary events in stable angina patients treated with nicorandil compared with placebo as add-on to conventional therapyAlso used in unstable angina. It also reduces the number of further attacksAdditive effects with nitratesRho kinase inhibition: FasudilRho kinase triggers vasoconstriction through accumulation of phosphorylated myosinAdapted from Seasholtz TM. Am J Physiol Cell Physiol. 2003;284:C596-8.Ca2+Ca2+PLCSR Ca2+ReceptorAgonistMyosinMyosin-PMyosin phosphatasePIP2IP3MLCKVOCROCCa2+CalmodulinRhoRho kinaseFasudil44The role of Ca2+ in activating myosin light chain kinase (MLCK) and phosphorylating myosin to cause contraction is well known.Dephosphorylation by myosin phosphatase causes subsequent dilation.More recently, the involvement of Rho kinase has been identified.In the absence of increases in intracellular Ca2+, Rho (a member of the Ras superfamily of small G proteins) activates Rho kinase, which in turn deactivates myosin phosphatase. This causes accumulation of phosphorylated myosin.Other abbreviations used in the figure:IP3 = inositol triphosphatePIP2 = phosphatidylinositol biphosphatePLC = phospholipase CROC = receptor-operated channelSR = sarcoplasmic reticulumVOC = voltage-operated channelRho kinase inhibition: FasudilFasudil up to 80 mg three times daily significantly increased the ischemic threshold of angina patients during exercise with a trend toward increased exercise duration.Double-Blind, Placebo-Controlled, Phase 2 Trial on 84 patients

J Am Coll Cardiol. 2005;46(10):1803-1811Molsodomine & linsodomine Anti anginal and anti ischaemic Acts like nitratesMetabolises in liver to form linsodomineOrally activeMetabolised in liver

TMLRSurgicalsurgeons use the laser to make holes between 20 and 40 tiny (one-millimeter-wide)Surgical incision madeDone along with CABG sometimes

47

48

49Percutaneous TMR

50RationaleImproved perfusion by stimulation of angiogenesisPotential placebo effectAnesthetic effect mediated by the destruction of sympathetic nerves carrying pain-sensitive afferent fibersPeri-procedural infarction.

51TMLR - Transmyocardial Laser RevascularizationHigh power CO2 YAG and excimer laser conduits in myocardial to create new channels for blood flowPossible explanations for effectMyocardial angiogenesisMyocardial denervationMyocardial fibrosis with secondary favorable remodelling

52TMLR Direct TrialOnly major blinded study298 pts with low dose, high dose, or no laser channelsNo benefit to TMLR vs Med therapy to Patient survivalAngina classQuality of life assessmentExercise durationNuclear perfusion imaging Leon MB, et al. JACC 2005; 46:1812High Surgical Risk (Mortality 5%)Mainly used as adjunct therapy during CABG to treat myocardial that cannot be bypassed.

EECP54EECPIncreases arterial blood pressure and retrograde aortic blood flow during diastole (diastolic augmentation).

Cuffs are wrapped around the patients legs and sequential pressure (300mmHg) is applied in early diastole.3 pairs of cuffs55Patient selectionAngina class III/IV Refractory to medical therapyReversible ischemia of the free wallnot amenable for revascularizationExcluded if LVEF