Role of Nitrates in ACS & Heart Failure

1. Role of Nitrates in ACS & Heart Failure Doni Firman

2. Acute Coronary Syndrome Definition: a constellation of symptoms related to obstruction of coronary arteries with chest pain being the most common symptom in addition to nausea, vomiting, diaphoresis etc. Chest pain concerned for ACS is often radiating to the left arm or angle of the jaw, pressure-like in character, and associated with nausea and sweating. Chest pain is often categorized into typical and atypical angina.

3. Definition • Generally described as retrosternal heavy or gripping sensation with radiation to left arm or neck, provoked by exertion and eased with rest or nitrates

4. Acute coronary syndrome • Based on ECG and cardiac enzymes, ACS is classified into: • STEMI: ST elevation, elevated cardiac enzymes • NSTEMI: ST depression, T-wave inversion, elevated cardiac enzymes • Unstable Angina: Non specific EKG changes, normal cardiac enzymes

5. Angina can be: • Stable • Unstable caused by unstable plaque, occurs at rest, unpredictable, pain can increase for no obvious reason • Prinzmetal’s occurs without provocation, usually at rest, as a result of coronary artery spasm

6. EKG • NSTEMI: • ST depressions (0.5 mm at least) or T wave inversions ( 1.0 mm at least) without Q waves in 2 contiguous leads with prominent R wave or R/S ratio >1. • Isolated T wave inversions: • can correlate with increased risk for MI • may represent Wellen’s syndrome: • critical LAD stenosis • >2mm inversions in anterior precordial leads • Unstable Angina: • May present with nonspecific or transient ST segment depressions or elevations

7. Etiology and pathogenesis • Symptoms are results of myocardial ischemia due to insufficient blood flow through atherosclerotically changed coronary vessels

8. IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Local factors • Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 • Blood flow patterns, vessel diameter, arterial wall structure Systemic conditions • History of vascular events • Hypertension • Hyperlipidemia • Hypercoagulable states • Homocystinemia Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) • Generalized • disorders • Obesity • Diabetes Genetic • Genetic traits • Gender • Age Lifestyle • Smoking • Diet • Lack of exercise Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6.

9. IMBALANCE BETWEEN MYOCARDIAL OXYGEN DEMAND AND SUPPLY Myocardial Oxygen demand Myocardial Oxygen supply

10. * Patency of coronary arteries/severerity of stenosis.* Coronary perfusion ie : diastolic blood pressure.* Hemoglobin : anemia, pathological Hb.* Oxygen saturation.* Heart rate : diastolic filling periode WHAT IS MYOCARDIAL DELIVERY / SUPPLY ?

11. * pre load : increase end diastolic volume, increase left ventricular wall stress.* after load : systolic blood pressure.* contractility : Left ventricular mass, heart rate. WHAT IS MYOCARDIAL DEMAND/REQUIREMENT ?

12. Diagnosis Clinical Evaluation of Patients With Chest Pain

13. Diagnosis Resting Electrocardiography to Assess Risk

14. Investigations • Laboratory tests (leukocytes, hemoglobin, thyroid hormones, troponin I and T, MB-CPK) • Resting ECG • Excercise ECG • Cardiac scintigraphy • Echocardiography • Coronary angiography

15. Guideline

16. Diagnosis of Patients with Suspected Ischemic Heart Disease

17. Treatment • Prognostic therapy: DAPT, lipid-lowering therapy • Symptomatic treatment: GTN, beta-blockers, long-acting nitrates, calcium-channel blockers, ACEI • Percutaneous coronary intervention, coronary artery bypass grafting

18. GLYCERIL TRINITRATE ISOSORBID DINITRATE ISOSORBID MONONITRATE Oral, sub lingual , IV Oral, sublingual , IV Oral Pro drugs Pro drugs active metabolisme Require hepatic convertion Require hepatic conversion isn”t subyect to hepatic metabolism to mononitrate metabolism to mononitrate metabolism Rapid onset, rapid effect Rapid onset, slow effect Slow onset, slow effect onset : 1 – 4 min. onset : 5- 10 min onset : 30 – 45 min. effect : 10 – 30 min. effect : up to 60 min. effect 12 – 14 hours For angina acut and prophylactis For angina acut and prophylactis For angina prophylactis Comparation of organic nitrate

20. ACTION OF NTG in ANGINA PECTORIS SYSTEMIC CIRCULATION 2.REDUCED AFTER LOAD 3. DILATED CORONARY ARTERY REDUCED RESISTANCE VESSELS 1. REDUCED PRELOAD ISCHEMIC ZONE DILATED INCREASE CAPACITANCE VESSELS REDUCED VENOUS RETURN

22. Adverse effects: • The most common side effect of nitrates is headache due to veno-dilation, patients whom intermittently used nitrate preparation should be asked about headaches after nitrate use; lack of headache often indicates degradation of agent with a loss of therapeutic effect. • Postural hypotension & syncope particularly with sublingual use. • Tachycardia induced by decreased PVR may itself induce anginal symptoms especially with unstable symptoms. • Methemaglobinemia can occur with chronic use of long term agents, this may occur when sublingual use is combined with long acting agents. • Withdrawal symptoms may occur (an indication of tolerance) when nitrate agents are tapered or discontinued, this may precipitate anginal attacks.

23. * The function of the heart is to pump an adequate volume of blood ( which it receives from the veins) to various tissues of the body as required by metabolic need.* Heart failure impaires the heart ability to pump effectively to maintain sufficient circulation to meet the body needs. Heart failure

24. CONTRACTILITY PATHOPHYSIOLOGY OF HEART FAILURE FILLING PRESSURE(PRE LOAD) INCREASE ARTERIAL IMPEDANCE ( AFTER LOAD ) INCREASE CARDIAC OUTPUT DECREASE INCREASE SYSTEMICVASCULAR RESISTANCE COMPENSATORY RESPONSES 1. Activation of sympathoadrenal system 2. Activation of RAA system 3. Renal mechanisms for consevation of sodium and water ec. anti diuretic hormon

28. NITRATES • Venodilation •  decreased diastolic heart size and fiber tension • Arteriolar dilation •  reduced peripheral resistance and BP • Overall reduction in myocardial fiber tension, O2 consumption and double product • No direct effects on the cardiac muscle • Can cause reflex tachycardia and increased force of contraction when reducing BP

29. CONTRACTILITY THE ROLE OF NITRATE IN HEART FAILURE FILLING PRESSURE ( PRE LOAD ) DECREASE ARTERIAL IMPEDANCE ( AFTER LOAD ) DECREASE CARDIAC OUTPUT DECREASE DECREASE SYSTEMICVASCULAR RESISTANCE NITRATE COMPENSATORY RESPONSES NITRATE • 1. Activation of sympathoadrenal system • Activation of RAA system • Renal mechanisms for consevation of sodium and water ec. Anti diuretic hormon

30. JACC: Heart Failure Vol. 1, No. 3, 2013

31. Summary • The organic nitrates are a safe and effective choice for the management of ischemic syndromes related to coronary heart disease • In the absence of arterial hypotension, organic nitrates are effective in management of acute and chronic heart failure

32. Thank You

33. JACC: Heart Failure Vol. 1, No. 3, 2013

34. Stable angina pectoris • Provoked by physical exertion, especially in cold weather, after meals and commonly aggravated by anger or excitement • The pain fades quickly with rest • In some patients pain occurs predictably at a certain level of exertion

35. Unstable Angina • Occurs at rest and prolonged, usually lasting >20 minutes • New onset angina that limits activity • Increasing angina: Pain that occurs more frequently, lasts longer periods or is increasingly limiting the patients activity

36. Case 1 • A 54 year old man with DM, HTN, and high cholesterol presents to the ER complaining of substernal chest pain. The pain feels like his chest is being squeezed. He first noted it two months ago when carrying packages up a flight of stairs. Last week he noticed it when walking to work. The past two days, the pain has occurred whenever he climbs the stairs in his house. This morning it occurred while driving to work. • His initial EKG shows sinus tachycardia with anterior ST depressions. • His initial cardiac biomarkers are negative. • He becomes pain free during his first few minutes in the ER and his EKG changes resolve.

37. Case 1 • Is this an ACS? • YES!!! • How should this patient be managed? • Morphine and NTG to make him pain free • Aspirin, Beta blocker, Heparin, Integrillin • Plan for catheterization with 24-48 hours

38. Case 2 • A 75 yom with HTN presents to the ER complaining of squeezing, substernal chest pain. The pain began this morning while taking a shower and has waxed and waned all day (~10 hours time). • Initial EKG shows sinus tachycardia without ST changes • Initial biomarkers: • CK 300, MB 20, Trop T 0.5

39. Case 2 • Is this an ACS? • YES!!! • How should this patient be managed? • Morphine and NTG to make him pain free • Aspirin, Beta blocker, Heparin, Integrillin • Plan for catheterization within 24-48 hours

40. References • 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005;112:IV-89-IV-110 • 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction : A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013, epublished April 29th 2013 and print published june 4th 2013. • Herman LK, et al. Comparison of frequency of inducible myocardial ischemia in patients presenting to emergency department with typical versus atypical or nonanginal chest pain. Am J Cardiol. 2010 105:1561-4.

41. Stable angina pectoris • Provoked by physical exertion, especially in cold weather, after meals and commonly aggravated by anger or excitement • The pain fades quickly with rest • In some patients pain occurs predictably at a certain level of exertion

42. Unstable Angina • Occurs at rest and prolonged, usually lasting >20 minutes • New onset angina that limits activity • Increasing angina: Pain that occurs more frequently, lasts longer periods or is increasingly limiting the patients activity

43. MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Ischemic stroke Transient ischemic attack Myocardial infarction Angina: • Stable • Unstable Peripheral arterial disease: • Intermittent claudication • Rest Pain • Gangrene • Necrosis Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6.

44. Clinical symptoms • Patient history is a˝golden standard˝ • Retrosternal pain • Dyspnea • Nausea • Arrhythmia • Restlessness • Levine sign • Pain eased after taking nitrates

45. 71-year-old female • Cardiovascular risk factors • Hypertension diagnosed more than 15 years before. CORONARY ANGIOGRAPHY : THREE VESSELS DISEASE

46. Comparing Pretest Likelihood of CAD in Low-Risk Symptomatic Patients With High-Risk Symptomatic Patients (Duke Database) Each value represents the percentage with significant CAD. The first is the percentage for a low-risk, mid-decade patient without diabetes mellitus, smoking, or hyperlipidemia. The second is that of a patient of the same age with diabetes mellitus, smoking, and hyperlipidemia. Both high- and low-risk patients have normal resting ECGs. If ST-T-wave changes or Q waves had been present, the likelihood of CAD would be higher in each entry of the table.

47. Noninvasive Risk Stratification *Although the published data are limited; patients with these findings will probably not be at low risk in the presence of either a high-risk treadmill score or severe resting LV dysfunction (LVEF <35%).

48. Algorithm for Risk Assessment of Patients With SIHD* *Colors correspond to the ACCF/AHA Classification of Recommendations and Levels of Evidence Table.

49. Algorithm for Risk Assessment of Patients With SIHD (cont.)* *Colors correspond to the ACCF/AHA Classification of Recommendations and Levels of Evidence Table.

50. CAD Prognostic Index *Assuming medical treatment only.