Advanced therapies for Refractory angina Dr. V. Vanaja, MD, DM Professor of Cardiology, SVIMS, Tirupati. WCC&IVUS2015
Definition • Patients with advanced chronic CAD having severe symptoms despite optimal medical therapy and further revascularisarion options are limited. • “A chronic condition (≥3 months) characterized by the presence of angina caused by coronary insufficiency in the presence of CAD, which is not amenable to a combination of medical Rx, PTCA,or CABG” in patients with evidence of ischemia. (ESC Joint study group) WCC&IVUS2015
Epidemiology • Incidence - 10 – 15% of patients undergoing cardiac cath. • Annual mortality - 3 – 4% WCC&IVUS2015
Proposed Phenotypes Phenotype Specifications A. Suspected coronary syndrome 1.Normal coronary angiogram with suspected coronary X syndrome X 2.Suspected CSX with prior CABG B. Limited territory at risk 1.Limited Territory at risk with no prior CABG surgery 2.Limited territory at risk with prior CABG C. Diffuse thread-like Diffuse atherosclerosis from proximal to distal beds atherosclerosis leading to a thread-like appearance with small (< 1mm) distal runoff. Typically involves simultaneously the 3 coronary arteries. Focal plaques possible but usually part of a diffuse process. D. End stage CAD A state of coronaropenia that combines stenosis in proximal coronary segments and a diffuse atherosclerosis of the distal coronary beds. A furnished network of coronary collaterals is typically visible in viable territories. Most frequently seen in with prior degenerated CABG WCC&IVUS2015
Treatment Goal Symptom Control Improving life expectancy Improving Quality of life. WCC&IVUS2015
Therapeutic principles of management Three principles : Reduction in LV oxygen consumption, Augmentation of coronary arterial blood flow, Maximising oxygen-carrying capacity of the blood. WCC&IVUS2015
General Measures for the Treatment of Refractory Angina WCC&IVUS2015
Management of Refractory Angina 1. Novel Pharmacologic therapy. 2. Non invasive therapy. 3. Invasive therapy. 4. Self Management Training WCC&IVUS2015
Treatment options for refractory angina WCC&IVUS2015
Novel Pharmacological therapies 1. Oxygen-sparers Allopurinol • Inhibits xanthine oxidase and associated oxidative stress. WCC&IVUS2015
2. Late Na + current inhibitors Ranolazine (IIa-B) • Inhibits late inward Na+current • Improves regional coronary blood flow in areas of myocardial ischemia. • Partially inhibit mitochondrial fatty-acid oxidation . WCC&IVUS2015
3. Partial fatty-acid oxidation inhibitors A. Perhexiline • Inhibits carnitine O-palmitoyltransferase 1 and 2 (transfer free fatty acid from the cytosol into mitochondria). • Inadequately investigated in patients with IHD. • Growing clinical experience in patients with CHF. • Plasma concentration required for dose titration. • Limited use because of Neuropathy, Hepatotoxicity. WCC&IVUS2015
B. Trimetazidine (IIb-B) • Reversibly inhibits mitochondrial long-chain 3-ketoacyl- CoA thiolase, an important enzyme in fatty-acid β -oxidation in mitochondria. • Chronic use has been associated with extra pyramidal adverse reactions, including Parkinsonism, gait disorders, and restless leg syndrome. WCC&IVUS2015
4. Vasodilator A. l-Arginine • Improves coronary blood flow via nitric-oxide mediated, endothelium-dependent vasodilatation. • Inadequately investigated in patients with IHD WCC&IVUS2015
B. Fasudil and hydroxyfasudil • Inhibit Rho kinase(reduces calcium sensitization of vascular smooth muscle). • anti-ischemic effects. • Currently available in Japan for prevention of CNS vasospasm associated with subarachnoid haemorrhage. • Potentially useful for vasospastic angina. WCC&IVUS2015
C. Molsidomine • Direct nitric oxide donor (sydnonimine), which vasodilates the coronary vasculature. • Anti anginal effect. WCC&IVUS2015
D. Nicorandil (IIa-B) • Nitrate-like effect that vasodilates the coronary vasculature and venous system. • Cardio protective effects (opening of mitochondrial ATP- sensitive potassium channels). WCC&IVUS2015
5. I f channel blockers Ivabradine (IIa-B) • reduce the automaticity of spontaneous depolarization in the SA node cells. • Vasodilatory effect. • Side effects: headache, dizziness, and brightness in the visual field. WCC&IVUS2015
6. Antidepressants A. Escitalopram : • Reduces mental stress-induced hemodynamic response (coronary artery vasoconstriction and microvascular changes). • Reduces platelet aggregation • anti-ischemic effect. B. Imipramine • Analgesic effect on the visceral component associated with cardiac pain • Investigated in patients with cardiac syndrome X and was shown to improve symptoms, but not quality of life. • Inadequately studied in patients with advanced CAD and refractory angina. WCC&IVUS2015
7. Chelation therapy EDTA • Mechanism of action uncertain, possibly associated with reduced oxidation of LDL, vasodilatory effects , and enhanced production of Tpa. 8. Rheological agents Intermittent thrombolytics (urokinase) : • Depletion of plasma fibrinogen (reduces blood viscosity and improves the rheological properties of blood in the microcirculation). 9. Testosterone • Promotes endothelium-dependent relaxation of coronary arteries. WCC&IVUS2015
Non-invasive therapies A. Enhanced external counter pulsation (EECP) B. Extracorporeal shock wave therapy(ESWT) C. Transcutaneous electrical neural stimulation [TENS] D. Subcutaneous electrical nerve stimulation [SENS] WCC&IVUS2015
Enhanced external counter pulsation (EECP) • (IIa-B) Inflation and deflation of compressive cuffs wrapped around the patients calves, lower thighs and upper thighs timed to the cardiac cycle. • Inflates during diastole (augments coronary blood flow) and deflates in systole (decrease afterload and increase venous return). • Benefits : – Recruitment of myocardial collaterals through activation of growth factors, – improvement of endothelial function, – the release of proangiogenic cytokines. – Increase in the level of nitric oxide, – Decrease in the level of endothelin, – Increase in the level of circulating CD34+ stem cells. WCC&IVUS2015
Enhanced external counter pulsation (EECP) • Protocol: Thirty-five 1-hour sessions. • Contraindications: – decompensated HF, – severe PAD, – abdominal aortic aneurysm, – severe aortic insufficiency. • MUST-EECP trial : demonstrated that time to exercise- induced ST-depression increased significantly and angina was less frequent in patients receiving EECP. WCC&IVUS2015
Extracorporeal shockwave therapy [ESWT] • Uses low-intensity shock waves (one-tenth the strength of those used in lithotripsy) that are delivered to myocardial ischemic tissue. • Shock waves, created by a special generator, are focused using a shock wave applicator device. • Done under Echo guidance. • The shock waves are delivered in synchronization with the patient’s R -wave. WCC&IVUS2015
Extracorporeal shockwave therapy [ESWT] • The stress wave and the cavitation effect induce local shear stress, which promotes expression of chemoattractants (stromal cell-derived factor 1, vascular endothelial growth factor), and nitric oxide. • In six small, randomized trials with a total of 240 patients improvement in symptoms, quality of life, ischemic thresholds and safety have been reported. WCC&IVUS2015
Transcutaneous electrical neural stimulation [TENS] • TENS involves applying a low-voltage electrical current via pads placed on the skin in the area of pain. • It stimulates large-diameter afferent fibers and inhibits input from small-diameter fibers in the substantia gelatinosa of the spinal cord. • An increased endorphin concentration in blood and cerebrospinal fluid has also been proposed. • Advantage: passive, noninvasive, and nonaddictive modality with no potentially harmful side effect. WCC&IVUS2015
Transcutaneous electrical neural stimulation [TENS] • In a small series of patients with pacing-induced angina, TENS demonstrated an increased tolerance to pacing, improved lactate metabolism, and less-pronounced ST- segment depression. • No data on the long-term efficacy. WCC&IVUS2015
Subcutaneous electrical nerve stimulation [SENS] • fairly new method to treat refractory angina • SENS targets subcutaneous nerve endings located in the precordial regions, from where the angina radiates. • Multipolar electrodes are subcutaneously implanted in the parasternal area, where patients typically feel anginal pain, and tunnelled to a pulse generator located in the upper abdomen. WCC&IVUS2015
Subcutaneous electrical nerve stimulation [SENS] • In a pilot study, Buiten and colleagues demonstrated the safety and feasibility of the concept using a stimulation protocol of three periods of ≥1 h daily. • All patients experienced reductions in the frequency of angina and sublingual nitrate consumption. WCC&IVUS2015
Invasive therapies A. Recanalization of CTOs B. Spinal cord stimulation(SCS) C. Transmyocardial laser revascularization(TMLR) D. Percutaneous Myocardial Laser Revascularization(PMLR) E. Cardiac Sympathectomy F. Coronary sinus reduction G. Therapeutic angiogenesis H. Heart transplantation WCC&IVUS2015
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