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REFRACTORY ANGINA....................pptx
- 1. REFRACTORY ANGINA DR SFURTIJADHAV SSSIHMS, WHITEFIELD
- 2. SCOPE OF PRESENTATION Introduction Definition of refractory angina Mechanisms of angina Prevalence Mechanism & pathophysiology of refractory angina Evaluation Treatment - Pharmacological & Non-pharmacological
- 3. Introduction Angina Greek– ancina- means strangulation Latin – ang – to throttle A sensation of choking or strangulation
- 4. Described byWilliam Heberden in 1772 A significant number of patients remain symptomatic in spite of anti-anginal drugs and/or after PCI or CABG
- 5. Definition The 2019ESC Guidelines for the Diagnosis and Management of Chronic Coronary Syndromes define refractory angina as follows: ‘Refractory angina refers to long-lasting symptoms (for >3months) due to established reversible ischaemia in the presence of obstructive coronary artery disease (CAD), which cannot be controlled by escalating medical therapy with the use of2nd- and 3rd-line pharmacological agents, bypass grafting, or stenting including PCI of chronic total coronary occlusion
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- 8. The elicited painfulstimuli travel through sympathetic (passing by the dorsal root ganglion) or vagal afferents (passing by the nucleus of tractus solitarius) to reach the posterior thalamus
- 9. Prevalence RAP prevalenceis estimated to be 5% to 10% in stable CAD patients Epidemiology is rapidly changing – d/t aging population with more prevalent CAD and of the widespread access to coronary revascularization
- 10. Mechanisms of refractoryangina Microvascular dysfunction Non revascularisation Non – obstructive causes –Vasospasm/ extramural compression Restenosis Non Coronary causes of angina Maladaptive pain perception
- 11. Microvascular dysfunction Myocardialblood flow - dependant on 1. Intraventricular , intramyocardial and right atrial pressures during the cardiac cycle 2. Anatomical and functional integrity of the coronary microvasculature
- 12. Type 5 –post- cardiac transplant
- 13. Non revascularisation 1. Poortargets/ technically unfeasible 2. CTO 3. High procedural risk 4. Collateral dependant circulation 5. Degenerated SVG 6. Restenosis
- 14. Non obstructive CAD Ischaemia with non-obstructive coronary artery disease appears to be particularly common in women and after PCI In patients with microvascular coronary spasm and documented ischaemia, an acetylcholine or ergonovine challenge may be useful to detect vasomotor dysfunction as the underlying cause
- 15. Myocardial Bridge Theircontribution to myocardial ischaemia, however, is controversial as more than 80% of myocardial blood flow occurs during diastole rather than systole Under certain conditions, particularly at higher heart rates and marked myocardial inotropism, muscle bridges may cause ischaemia either directly or by inducing spasm
- 16. Evaluation Confirm anginalsymptoms & assess severity – mild – conservative approach CTCAG Functional imaging – Stress Echo/ Stress MRI/ MPI – SPECT/PET CT FFR FFR – also evaluates myocardial bridge
- 17. Optimal medical management Optimal treatment can be defined as the treatment that satisfactorily controls symptoms and prevents cardiac events associated with CCS, with maximal patient adherence and minimal adverse events Lifestyle modification Pharmacotherapy – Antianginal therpy
- 18. Lifestyle modification Smokingcessation Healthy diet Physical activity Healthy weight Others
- 19. Lifestyle factor Smoking cessationUse pharmacological and behavioural strategies to help patients quit smoking.Avoid passive smoking. Healthy diet Diet high in vegetables, fruit, and wholegrains. Limit saturated fat to <10% of total intake. Limit alcohol to <100 g/week or 15 g/day. Physical activity 30 60 min moderate physical activity most days, but even − irregular activity is beneficial. Healthy weight Obtain and maintain a healthy weight (<25 kg/m2 ), or reduce weight through recommended energy intake and increased physical activity Other Take medications as prescribed. Sexual activity is low risk for stable patients not symptomatic at low-to-moderate activity levels
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- 23. a) Combination ofa BB with a DHP-CCB should be considered as first step; combination of a BB or a CCB with a second-line drug may be considered as a first step b) The combination of a BB and non-DHP-CCB should initially use low doses of each drug under close monitoring of tolerance, particularly heart rate and blood pressure c) Low-dose BB or low-dose non-DHP-CCB should be used under close monitoring of tolerance, particularly heart rate and blood pressure d) Ivabradine should not be combined with non-DHP-CCB e) Consider adding the drug chosen at step 2 to the drug tested at step 1 if blood pressure remains unchanged.
- 24. Beta –blockers – dose limit the heart rate to 55 - 60 b.p.m. CCBs –Non DHP – Rate ↓ / peripheral vasodilation / relief of exercise induced constriction, modest negative inotropic effect & sinus node inhibition For verapamil, compared with metoprolol, the antianginal activity was similar & compared with atenonol in hypertension with CAD, it is associated with fewer cases of diabetes, fewer anginal attacks & less psychological depression CCB- DHP – In patients with CCS and normal BP (75% receiving a beta- blocker), amlodipine 10 mg/day reduced coronary revascularizations and hospitalizations for angina in a 24 month trial Long acting nitrate – 2nd line therapy
- 25. Novel pharmacological therapies Ivabradine – second line Adding ivabradine 7.5 mg b.i.d. to atenolol therapy gave better control of heart rate and anginal symptoms non-inferior to atenolol or amlodipine in the treatment of angina and ischaemia in patients with CCS –no mortality benefit Nicorandil – second line Ranolazine – second line Trimetazidine – no hemodyanmic effects Perhexiline , allopurinol, fasudil
- 31. Lipid apheresisis an extremely effective method to reduce LDLcholesterol as well as other lipids such as lipoprotein(a). Lipid apheresis treatment improves endothelial function in the forearm circulation within hours is similarly effective, albeit much more burdensome to the patient, as PCSK9 inhibition Improves myocardial perfusion reserve and symptoms in patients with elevated lipoprotein(a) levels (>500 mg/L) and refractory angina
- 34. Non pharmacologic therapy Revascularisation strategies PCI Transmyocardial laser revascularization Unroofing of myocardial muscle bridges Radiation therapy for recurrent restenosis Cardiac rehabilitation EECP Coronary sinus occlusion Extracorporeal shockwave myocardial revascularization Spinal cord stimulation Stem Cell Therapy Chelation Therapy
- 35. PCI CTOs arequite common and today they can be approached with new percutaneous revascularization techniques
- 36. The EuroCTO trial (A Randomized Multicenter Trial to Evaluate the Utilization of Revascularization or Optimal Medical Therapy for the Treatment of Chronic Total Coronary Occlusions) randomized 407 patients to CTO PCI vs. optimal medial therapy alone. At 12 months, compared with patients randomized to medical therapy only, those randomized to CTO PCI had greater improvement in angina frequency with a subscale change difference: 5.23, and quality of life (subscale change difference: 6.62), as assessed by the Seattle Angina Questionnaire
- 38. Whether CTOPCI improves traditional composite endpoints of death, myocardial infarction, stroke, or revascularization - undetermined
- 39. Transmyocardial laser revascularization Transmyocardial laser revascularization (TMLR) Creates channels in the ischaemic myocardium to restore perfusion Up-regulate of vascular endothelial growth factors (VEGFs) to stimulate angiogenesis Myocardial sympathetic denervation to blunt angina
- 42. Unroofing of myocardialmuscle bridges
- 43. Radiation therapy forrestenosis
- 47. Enhanced external counterpulsation Enhanced external counterpulsation (EECP) uses externally applied blood pressure cuffs on both legs that are intermittently inflated up to 300mmHg during early diastole, first in the lower legs, followed by inflation of those placed on the lower and upper thighs Similar to IABP – Diastolic augmentation On the venous side, EECP augments right ventricular filling pressure due to an increased venous return. Typically, a full course of therapy consists of 35 sessions of 1 hour each
- 49. In theMUST-EECP trial that enrolled 139 patients with angina pectoris and a positive treadmill test received 35 h of EECP over 4–7weeks or inactive counterpulsation (sham group), EECP was safe and well tolerated, reduced angina pectoris and prolonged the time to exercise- induced ischaemia in thesepatients with refractory chest pain
- 50. EECP improvesperipheral endothelial function up to 1 month of follow-up in patients with a positive clinical response. This suggests that improved endothelial function contributes to the clinical benefits of EECP in patients with refractory angina
- 51. Coronary sinus occlusion In the 1950s and 1960s, the cardiac surgeon Claude Beck surgically narrowed the coronary sinus in patients with severe angina, to increase coronary sinus pressure and to achieve redistribution of myocardial blood flow into ischaemic territories
- 52. Coronary sinusreducer–Acts by elevating backward pressure in the coronary venous system results in a slight dilatation of arterioles leading to a significant reduction in vascular resistance in the subendocardial myocardium. Blood flow in the ischaemic subendocardium is enhanced, contractility improves, and left ventricular end diastolic pressure (LVEDP) decreases which further reduces resistance to flow in the sub-endocardial layers of the myocardium,which will lead to symptom relief.
- 53. The CoronarySinus ReducerVR is a balloon expandable stainless-steelmesh, designed to create a permanent focal narrowing in the lumen of the coronary sinus to generate a pressure gradient across it. The ReducerVR is implanted percutaneously via the right jugular vein into the coronary sinus. A few weeks after implantation, the gaps between the metal struts are covered with tissue ingrowth, to create the central narrowing and establish a pressure gradient across the device
- 54. The coronary sinusreducer. (A)The Reducer on the inflated balloon.The diameters of the proximal and distal ends of the Reducer are determined by the inflation pressure of the balloon.The narrowed centre of the device is always 3 mm. (B)The expanded Reducer after balloon deflation. (C) Coronary sinus angiography using a multipurpose diagnostic catheter at LAO 30 degrees. (D) Contrast injection through the guiding catheter while Reducer balloon inflation. Oversizing of the implanted Reducer is important. (E) Coronary sinus angiography immediately after Reducer implantation.
- 55. The COSIRA randomizedsham-controlled clinical trial demonstrated improvement of >_2 CCS class in 35% (18/52) of the Reducertreated patients vs. 15% (8/52) of the sham-control patients (P= 0.02), and improvement of at least 1 CCS angina class in 71% (37/52) vs. 42% (22/ 52) in the sham-control group (P= 0.003) (left). Mean CCS class improvement for the groups was from 3.2 to 2.1 in the treatment group and from 3.1 to 2.6 in the sham- controlled group (P=0.001) (right).
- 56. Extracorporeal shockwave myocardial revascularization Extracorporeal shockwave myocardial revascularization (ESMR) is a non-invasive emerging treatment that, through the application of targeted shockwaves, may improve myocardial perfusion and symptoms of refractory angina. Through a commercially available shockwave generator, pulses of shockwave energy are applied to the ischaemic myocardium.
- 59. Spinal Cord Stimulationand Transcutaneous Electrical Nerve Stimulation (TENS) The use of spinal cord/nerve stimulation for the treatment of RA bases on an alternative explanation for the source of the chest pain, i.e., that its cause might not reside within the myocardium, but rather originate from its elaboration within the somatosensory nervous system
- 60. The centralnervous system (CNS) is responsible for the perception of visceral chest pain, and it has been shown that patients who have been diagnosed with angina in the absence of coronary artery obstructions present characteristic regional differences in brain activation as compared to patients with ”traditional” CAD This appears to suggest that while angina in patients with CAD group is due to a supply–demand mismatch, the chest pain of patients with no CAD may be due to abnormal CNS processing of afferent signals from the myocardium, leading to inappropriate and increased cerebral cortex activation and the subjective feeling of pain.
- 61. Using across-over design in two parallel groups, the authors show that the Pw/Pa ratio increases during ischemia when electrical neurostimulation is active, while it decreases when it is inactive, an effect that might be due to collateral vessel recruitment via b-adrenergic receptors. Finally, some studies showed a reduction in afterload and systemic vasodilatation following SCS, possibly due to reduced sympathetic activity.
- 62. SCS isa surgical procedure that consists of implantation of one or more leads in the epidural space of the spinal canal. The lead(s) are connected to an implantable pulse generator and delivers on-demand a weak electrical current to the spinal cord, resulting in peripheral paresthesia and withdrawal of pain. Beyond RA, SCS is used for complex regional pain syndrome and radicular pain after failed back surgery syndrome, stump pain after amputation, and pain due to peripheral nerve injury, peripheral vascular disease, and diabetic neuropathy. Symptomatic success rates for these indications have been reported to be in the range of 50–75%.
- 63. The largestblinded study to date, STARTSTIM was underpowered, due to slow patient enrollment and subsequent early termination.The analysis of 68 patients failed to show the efficacy of SCS against control-group, showing significant improvement in both groups consistent with the placebo effect. Two recent meta-analyses of 14 and 12 studies in RA patients showed longer exercise duration, lower angina frequency and nitrate consumption associated with SCS. Future studies will have to test whether these effects are confirmed in larger cohorts. Imran,T.Fet al Efficacy of spinal cord stimulation as an adjunct therapy for chronic refractory angina pectoris. Int. J. Cardiol. 2017, Pan, X et al. Spinal Cord Stimulation for Refractory Angina Pectoris. Clin. J. Pain. 2017,
- 65. Stem cell therapy Cell therapy with bone marrow (BM)-derived progenitors has emerged as a promising therapeutic option for RA patients. Different BM autologous vasculogenic cell populations, including unfractioned mononuclear cells, CD34+ or CD133+ cells, have been injected into ischemic areas to ameliorate perfusion of LV territories not otherwise amenable to revascularization
- 66. Safety andfeasibility of intramyocardial injection of autologous CD34+ stem cells were demonstrated in a Phase I/IIa double- blind, randomized controlled trial on 24 RA patients, showing potential bioactivity with improvement in CCS angina class A phase II randomized trial, including 167 RA patients, showed a significant improvement in both angina symptoms and exercised tolerance with intramyocardial injection of autologous CD34+ stem cells over placebo at 6, 12 months with persistent results at 24 months follow-up In addition, there was a trend towards a reduction in the rates of major adverse cardiac events (p = 0.08)
- 67. Based onthese promising results, a phase III randomized (RENEW, efficacy and safety of targeted intramyocardial delivery of auto CD34+ stem cells for improving exercise capacity in subjects with refractory angina) trial was launched. However, the trial was terminated prematurely by the sponsor, due to financial reasons, recruiting only 112 patients of planned 444, which was not sufficient to test its efficacy end-point
- 68. Recognizing theweight of the TACT results, the American Heart Association and the American College of Cardiology upgraded edetate disodium chelation from a 3C to a 2B indication in their 2014 revision of the guidelines for the treatment of chronic ischemic heart disease.
- 69. However, 2019ESC guidelines for CCS for treatment of refractory angina have not included chelation therapy.
- 71. Trans-endocardial deliveryof another autologous bone marrow-derived cells, CD133+ cells, were proved to be safe and feasible in two small phase I randomized trials not powered for efficacy end-points Another recent phase I randomized trial of intramyocardial injection of CD133+ cells in RA patient subset with LV dysfunction (LV < 45%) confirmed the safety profile of the previous two trials and showed significant improvements in CCS angina class, myocardial perfusion and function assessed by single-photon emission computer tomography at 12 months
- 75. Chelation therapy Treatmentof lead toxicity with chelation was first reported with EDTA in the early 1950s. Apparent success in reducing metastatic calcium deposits led Clarke et al in 1956 to treat angina patients with EDTA, and others to use chelation for various forms of atherosclerotic disease. Chelation therapy evolved to constitute infusions of vitamins and disodium EDTA, a drug that binds divalent and some trivalent cations, including calcium, magnesium, lead, cadmium, zinc, iron, aluminum, and copper, facilitating their urinary excretion.
- 76. Three smallclinical trials have assessed the effects of chelation on surrogate outcomes, such as walking distance in patients with claudication (2 trials with 185 patients total) and time to exercise-induced ischemia in patients with coronary disease (1 trial with 84 patients). These studies did not find any evidence of treatment efficacy but were underpowered for evaluation of clinical events
- 86.