Advanced therapies for Refractory angina Dr. V. Vanaja, MD, DM - - PowerPoint PPT Presentation

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)

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Epidemiology

• Incidence - 10–15% of patients undergoing cardiac cath.
• Annual mortality - 3–4%

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Proposed Phenotypes

Phenotype Specifications

• A. Suspected coronary syndrome

X 1.Normal coronary angiogram with suspected coronary 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

atherosclerosis Diffuse atherosclerosis from proximal to distal beds 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

• f the distal coronary beds.

A furnished network of coronary collaterals is typically visible in viable territories. Most frequently seen in with prior degenerated CABG

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Treatment Goal

• Symptom Control
• Improving life expectancy
• Improving Quality of life.

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Therapeutic principles of management

Three principles:

• Reduction in LV oxygen consumption,
• Augmentation of coronary arterial blood flow,
• Maximising oxygen-carrying capacity of the blood.

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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

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Treatment options for refractory angina

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Novel Pharmacological therapies

1. Oxygen-sparers

• Allopurinol
• Inhibits xanthine oxidase and associated oxidative stress.

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• 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.

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• 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.

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• 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.

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• 4. Vasodilator
• A. l-Arginine
• Improves coronary blood flow via nitric-oxide mediated,

endothelium-dependent vasodilatation.

• Inadequately investigated in patients with IHD

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• 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.

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• C. Molsidomine
• Direct nitric oxide donor (sydnonimine), which vasodilates

the coronary vasculature.

• Anti anginal effect.

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• 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).

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• 5. Ifchannel 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.

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• 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.

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• 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.

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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]

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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.

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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.

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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.

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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.

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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.

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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

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Recanalization of chronic total occlusion

• Recommendations:
• 1. Unsuitable for CABG surgery,
• 2. symptomatic despite optimal medical therapy,
• 3. documented large ischemic burden.

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Spinal cord stimulation (SCS)

• A Multipolar electrode is surgically positioned in the epidural

space between the C7 and T4 vertebrae, near to the dorsal column where the myocardial afferent sympathetic fibers synapse with second-order sensory neurons in the dorsal horns.

• During SCS, the electrode is linked to a programmable pulse

generator.

• The therapy is self-administered and typically requires stimulation

for 1 h, three times per day, and whenever angina occurs. WCC&IVUS2015

Spinal cord stimulation (SCS)

• SCS (IIb-B) is thought to alter the dorsal-horn neurochemistry by

promoting the release of γ-aminobutyric acid, which antagonizes the effect of the descending inhibitory pathways that are known to favor the transmission of the nociceptive afference.

• SCS have a dual effect on angina (analgesic effect, sympatholytic

effect).

• Despite two positive systematic reviews and the ESC

recommendation, SCS is not approved in the USA. WCC&IVUS2015

Transmyocardial laser revascularization

• Developed according to the theory that channels in the myocardium

would carry blood from the ventricular cavity directly to the myocardium, similarly to those in reptilian hearts.

• The mechanism of benefit is more likely to be the result of injury

stimulating angiogenesis or denervation.

• TMLR is performed epicardially during a surgical procedure (open

chest or robotic) or endocardially via a Percutaneous approach (PTMLR) (IIb-B).

• TMLR, either alone or in conjunction with CABG surgery, is

approved by the FDA for the treatment of refractory angina. WCC&IVUS2015

Transmyocardial laser revascularization

• A series of open-chest surgical trials showed improvements

in angina, exercise time, and myocardial perfusion.

• In the PACIFIC trial,15 PTMLR and medical therapy was

compared with medical therapy alone in 221 patients with CCS class III angina. PTMLR was associated with an improvement in exercise tolerance.

• Contraindicated in patients with a low LVEF or recent MI.

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Cardiac sympathectomy

• The left stellate (cervicothoracic) ganglion is a readily accessible

point of convergence for sympathetic fibres that transmit the afferent cardiac pain signal to the intermediolateral grey column in the thoracic spinal cord en route to the central nervous system.

• Temporary sympathectomy by stellate ganglion blockade.
• Alternative routes for temporary (high thoracic epidural analgesia)

and permanent sympathectomy have also been used with varying success.

• Appropriate evidence is lacking.

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Coronary Sinus Reducer

• The balloon expandable, stainless steel, hourglass-

shaped, coronary-sinus reducing device creates a focal narrowing and increases pressure in the coronary sinus, thus redistributing blood into ischemic myocardium.

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Coronary Sinus Reducer for Treatment of Refractory Angina (COSIRA) trial

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Therapeutic Angiogenesis

• A. protein growth factors,
• B. gene therapy,
• C. stem-cell therapy.
• These techniques are supported by successful preclinical

studies in the setting of ischemic myocardium.

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• Protein therapy:
• Two large, randomized, placebo-controlled trials involving

intracoronary VEGF and fibroblast growth factor (FGF) showed no efficacy in terms of the primary end point (exercise time), but positively affected the secondary end points (angina and quality of life) in patients with angina.

• A short half-life was the major limitation.

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• Gene Therapy:
• Intracoronary delivery of an adenovirus encoding FGF5

(Ad5FGF) was successful in the AGENT-1 and AGENT-2 trials.

• AGENT-3 and AGENT-4 were double-blind trails.
• Analysis of AGENT-3 and AGENT-4 showed no difference

in the primary end point, but did show a significant reduction in angina and a substantial exercise benefit in high-risk patients. (age >55 years, angina class III–IV, baseline exercise time <300 s).

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• Cell therapy
• can promote neovascularization and consequently improve

myocardial perfusion and contractile function.

• Mechanism of benefit:
• 1. differentiation or regeneration,
• 2. paracrine effects ( alter myocardial function, reduce

apoptosis, and recruit both resident and circulating stem cells).

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• Cell therapy
• A systematic review and meta-analysis of nine randomized

trials indicated that cell therapy might significantly reduce mortality over 6–12 months and reduce angina symptoms. Potential future directions

• delivery via retroperfusion in the coronary sinus,
• gene-modification of cells to enhance their cytoprotective and

proangiogenic properties,

• allogeneic cells, cardiac-derived cells, or pluripotent cells.

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HEART TRANSPLANTATION

• For patients who have disabling angina and in whom all

conventional and alternative treatment modalities have failed.

• One year survival is 80%, with an average 10-year survival rate
• f 40% .

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Self management training

The CSC practice guidelines on refractory angina mention self-management training as an evidence-based treatment that can be considered to reduce angina symptoms and the associated use of nitrates, and to improve quality of life.

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Conclusions

• Patients with advanced CAD and refractory angina are a

complex and growing population.

• Aggressive risk-factor modification, antianginal medications,

and revascularization has resulted in a substantial improvement in their long term survival.

• A growing number of novel pharmacological, noninvasive,

and invasive therapeutic modalities are under investigation, with the aim of improving quality of life.

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Thank you

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