Overview
A case-based briefing on the pharmacology of ischaemic heart disease, built around Mr M.I., an 85 year old man who develops crushing chest pain on day 2 after a hip replacement. The lecture sets out the spectrum of coronary syndromes from stable angina through to STEMI, the pathophysiological sequence that generates them, the principles that govern drug choice (restoring the myocardial oxygen supply/demand balance), the immediate management of an acute MI including the reperfusion decision between PCI and thrombolysis, and the long term secondary prevention plan. It is a briefing to be prepared in advance: much of the drug detail is left for discussion rather than stated on the slides.
Scope and learning targets
- The case is meant to support and reinforce learning from the prior lectures and contains relevant information on angina and MI. Students read it in advance and come prepared to answer questions on pharmacological use and to discuss therapeutic reasoning.
- Objectives: understand the spectrum of coronary syndromes; work through the Mr M.I. case study; cardiovascular pharmacology in the setting of the coronary syndrome.
- The five drug classes flagged as the key learning targets (learn them in relation to MI and angina, and when to use each):
- Nitrates
- Antiplatelets and anticoagulants
- Thrombolytics / fibrinolytics
- Beta blockers
- ACE inhibitors / ARBs
- Reference material: ESC 2019 guidelines on the management of chronic coronary syndromes; Goodman and Gilman’s Manual of Pharmacology and Therapeutics, chapter 27, 14th edition (AccessMedicine via the library); physiology and anatomy material on the ECG and atherosclerosis.
Ischaemic heart disease: definition and spectrum
- Ischaemia is interruption of cardiac blood supply, primarily involving the epicardial coronary vessels.
- Cause of Ischaemic heart disease: coronary artery disease.
- The spectrum runs as a continuum from angina, which is painful but not life threatening, to acute MI, which is life threatening.
- The affected territory is supplied by the left coronary artery (LCA) or right coronary artery (RCA); the ischaemic myocardium is the region of wall distal to the affected vessel.
Types of angina
Angina arises from occlusion of the large epicardial coronary arteries. The slide contrasts four coronary artery cross sections in sequence:
| State | Coronary artery disease | Lumen |
|---|---|---|
| Normal | none | clear, open |
| Stable angina | chronic coronary artery disease | narrowed by fatty material deposited in the vessel wall |
| Unstable angina | acute coronary artery disease | blocked by a blood clot |
| Variant / Prinzmetal angina | not stated | shown by a different mechanism, neither plaque nor thrombus |
Warning
The variant/Prinzmetal angina cross section is shown struck through with no explanatory label, so the mechanism is not stated on the slide.
IHD categories
- Chronic coronary artery disease (CAD): stable angina.
- Acute coronary syndromes:
- Unstable angina
- NSTEMI (non-ST elevation MI; subendocardial)
- STEMI (ST elevation MI; transmural)
- Unstable angina, NSTEMI and STEMI are grouped together as a progression/spectrum within the acute coronary syndromes.
Pathophysiology and classification of acute coronary syndromes
Sequence, in order:
- Plaque disruption or erosion
- Thrombus formation, with or without embolisation
- Acute cardiac ischaemia
- Branch by ECG appearance into non-ST elevation and ST elevation
- Branch by serum marker status into the final diagnosis
| ECG | Serum markers | Diagnosis |
|---|---|---|
| Non-ST elevation | not elevated | unstable angina |
| Non-ST elevation | elevated | NSTEMI |
| ST elevation | elevated | STEMI |
The ECG is identical in unstable angina and NSTEMI, so these two cannot be separated on ECG alone and require serum markers to differentiate.
The case: presentation and assessment
- Setting: first long day as a house surgeon on the orthopaedic ward. At 9 pm you are paged to see Mr M.I., 85 years old, day 2 post hip replacement, very anxious and experiencing crushing chest pain. Consider the differentials for angina.
- The nurse reports a history of angina in the admission notes, and the patient says this pain feels similar.
- On examination he is an elderly gentleman who looks pale, diaphoretic and clearly in pain.
- Observations at the bedside:
| Measure | Value | Note |
|---|---|---|
| O2 saturation | 91% | |
| Heart rate | 126 bpm | |
| Respiratory rate | 22 breaths/min | normal 12 to 18 |
| Blood pressure | 155/90 mmHg | |
| cTnI | raised, 2.5 ng/ml |
- An ECG is arranged while the presentation is interpreted.
Warning
The 12 lead ECG shown (leads I, II, III, aVR, aVL, aVF, V1 to V6, with raised domed ST segments in several precordial leads) carries no on-slide labels or annotations of the abnormality, so the exact ECG findings are not stated by the slide.
Intervention principles in ischaemic heart disease
The aim is to re-establish the balance between myocardial oxygen supply and demand:
- Re-establish or increase oxygen supply, by increasing the duration of diastole and decreasing coronary resistance.
- Decrease myocardial oxygen demand (MVO2).
Pharmacology is used to reduce:
- Pain associated stress
- Heart rate if the patient is tachycardic, with caution in bradycardia
- Cardiac contractility, using drugs that decrease contractility, checking haemodynamics with echo
- Wall stress / work, via:
- Reduced preload: increase peripheral venodilation, decreasing venous return, allowing a reduction in end diastolic volume and improved coronary perfusion
- Reduced afterload: reduce blood pressure or decrease peripheral arteriolar resistance
Urgency: time is muscle
- Ischaemia in MI is progressive.
- Irreversible loss of myocardial tissue occurs after 45 minutes of ischaemia.
- Death is common within the first 2 hours following symptoms.
Important
These two figures are the justification for early intervention: the window before irreversible myocardial loss is 45 minutes, and the highest mortality is in the first 2 hours.
Immediate drug management in the case
Interventions given, in the order of the case:
- Intravenous line inserted and bloods taken.
- Morphine 2 mg, after checking whether he has had morphine in the past. Consider the value of morphine here and the adverse drug reactions associated with it.
- A sublingual puff of GTN.
- Low dose aspirin charted, with the caveat that the new hip joint may bleed.
Reperfusion: PCI versus thrombolysis
- On the basis of the initial ECG and clinical presentation, Mr M.I. is diagnosed with a STEMI.
- His heart needs immediate coronary revascularisation to restore blood flow. The interventional cardiologist offers two options:
- Immediate transfer to a coronary intervention unit for adjunctive PCI within 6 to 24 hours, OR
- Thrombolysis, if there are no contraindications.
- Criteria for high-risk PCI (ESC), in three groups:
- Patient related: age; heart failure; prior cardiac surgery; concomitant valve disease; diabetes; chronic obstructive disease; chronic kidney disease; peripheral vascular disease.
- Coronary anatomy: multivessel disease; unprotected left main; last remaining vessel; chronic total occlusion (CTO); calcified lesion; long lesion; complex bifurcation lesions.
- Haemodynamic status: increased LV end diastolic pressure; impaired cardiac output; lower mean arterial pressure; anticipated prolonged ischaemic time; large area of myocardium at risk; ventricular arrhythmias.
- Mr M.I. is considered unsuitable for PCI because he falls within the high-risk PCI parameters, and he is not suitable for CABG.
- The question then raised is whether he is suitable for fibrinolysis with rtPA (tenecteplase), given that he is over 75 years old and was post operative and had been treated with enoxaparin. The side effects of fibrinolytic agents are to be considered.
Warning
The slide bullet stating why he is not suitable for CABG is truncated in the source (“not suitable for CABG as a”), so the reason is not recoverable.
Adjunctive and long term therapy
- Adjunctive therapy: antiplatelets/anticoagulants and nitrates (both left for discussion rather than detailed on the slide).
- Long term treatment plan, aimed at reducing mortality and re-infarction:
- Secondary/tertiary care: PCI or coronary bypass.
- Drug classes for discussion: statins, ACE inhibitors, nitrates, aspirin, beta blockers, warfarin/dabigatran.
- At discharge: Mr M.I. survives and is discharged a week later with his new hip and a slightly damaged heart. He is booked for angiography. The task is to develop a long term post-STEMI pharmacological management plan based on the NZ guidelines, and to consider management in stable angina and management in unstable angina/NSTEMI as separate scenarios.
Self-test
- Define ischaemia as it applies to ischaemic heart disease, and name its cause.
- Name the five drug classes highlighted as the key learning targets for MI and angina.
- Distinguish stable angina from unstable angina in terms of the state of the coronary lumen and the type of coronary artery disease.
- List the categories of ischaemic heart disease, grouping them into chronic coronary artery disease and acute coronary syndromes.
- Describe the steps of the pathophysiological sequence leading from a coronary plaque to acute cardiac ischaemia.
- A patient has an ECG showing no ST elevation and elevated serum markers. What is the diagnosis, and which other diagnosis shares an identical ECG?
- Explain why serum markers are required to separate unstable angina from NSTEMI.
- State the two aims of intervention in ischaemic heart disease, and how oxygen supply is increased.
- Explain how reducing preload improves the situation in ischaemic heart disease.
- Distinguish the mechanism of preload reduction from that of afterload reduction.
- What is the time after which irreversible loss of myocardial tissue occurs, and within what period following symptoms is death common?
- An 85 year old man on the orthopaedic ward, day 2 post hip replacement, is pale, diaphoretic and in crushing chest pain, with O2 sats 91%, HR 126, RR 22, BP 155/90 and cTnI 2.5 ng/ml. List the immediate drugs given in this case and the caution attached to one of them.
- List the three categories of high-risk PCI criteria, with two examples from each.
- Mr M.I. is unsuitable for PCI. Which features of his case are raised as relevant to whether fibrinolysis with tenecteplase is safe?
- List the drug classes named for the long term post-MI plan aimed at reducing mortality and re-infarction.
- Integrative: using the intervention principles, explain why a tachycardic patient in pain with an evolving STEMI is given analgesia, a nitrate and an antiplatelet early, and why the reperfusion decision cannot wait.
Answers
Reveal answers
- Ischaemia is interruption of cardiac blood supply, primarily involving the epicardial coronary vessels; the cause is coronary artery disease.
- Nitrates; antiplatelets and anticoagulants; thrombolytics/fibrinolytics; beta blockers; ACE inhibitors/ARBs.
- Stable angina is chronic coronary artery disease with fatty material deposited in the vessel wall narrowing the lumen; unstable angina is acute coronary artery disease in which the lumen becomes blocked by a blood clot.
- Chronic coronary artery disease: stable angina. Acute coronary syndromes: unstable angina, NSTEMI (non-ST elevation, subendocardial) and STEMI (ST elevation, transmural).
- Plaque disruption or erosion, then thrombus formation with or without embolisation, then acute cardiac ischaemia, which then branches by ECG into non-ST elevation and ST elevation and by serum markers into the final diagnosis.
- NSTEMI; unstable angina has an identical ECG.
- Because the ECG is identical in the two conditions (both non-ST elevation), so only the serum marker status distinguishes them: not elevated means unstable angina, elevated means NSTEMI.
- Re-establish or increase oxygen supply, and decrease myocardial oxygen demand (MVO2). Supply is increased by increasing the duration of diastole and decreasing coronary resistance.
- Increasing peripheral venodilation decreases venous return, which reduces end diastolic volume and improves coronary perfusion, so wall stress and work fall.
- Preload reduction works by peripheral venodilation reducing venous return and end diastolic volume; afterload reduction works by reducing blood pressure or decreasing peripheral arteriolar resistance.
- Irreversible loss of myocardial tissue after 45 minutes of ischaemia; death is common within the first 2 hours following symptoms.
- Morphine 2 mg intravenously (after checking previous morphine exposure), a sublingual puff of GTN, and low dose aspirin; the caution is bleeding from the new hip joint with aspirin.
- Patient related (for example age, heart failure, diabetes, chronic kidney disease); coronary anatomy (for example multivessel disease, unprotected left main, calcified or long lesions, complex bifurcation lesions); haemodynamic status (for example increased LV end diastolic pressure, impaired cardiac output, lower mean arterial pressure, large area of myocardium at risk).
- He is over 75 years old, he was post operative, and he had been treated with enoxaparin.
- Statins, ACE inhibitors, nitrates, aspirin, beta blockers, and warfarin/dabigatran, alongside PCI or coronary bypass in secondary/tertiary care.
- Analgesia removes pain associated stress and, with rate control, lowers myocardial oxygen demand; a nitrate produces peripheral venodilation that reduces preload and end diastolic volume, lowering wall stress and improving coronary perfusion; an antiplatelet targets the thrombus formed on the disrupted plaque that is generating the ischaemia. The reperfusion decision cannot wait because ischaemia in MI is progressive, with irreversible myocardial loss after 45 minutes and death common within the first 2 hours of symptoms.