The patient in context is a 61 year old male, Mr. X, admitted to hospital in the late evening for a case of unstable angina. Presenting complaints include left-sided chest pain which was less severe than that of his previous admission and localized pain during rest. Absent symptoms are profuse sweating as well as nausea and vomiting, orthopnea and paroxysmal nocturnal dypsnoea, cough and fever. Patient's past medical history includes diabetes mellitus and hypertension diagnosed 6 years ago, ischaemic heart disease (IHD) since 3 years ago, for which the last hospital admission was 11 months ago. In the previous admission for IHD, Mr. X also suffered from pneumonia and ventricular failure, his electrocardiogram (ECG) indicated right bundle branch block, his serum troponin I levels were 0.3 ng/mL (normal levels 0-0.1 ng/mL), and his creatinine levels were 5.0 mg/dL (normal for males 0.2-0.6 mg/dL). Mr. X is also afflicted with chronic kidney disease, for which his baseline creatinine during his last admission was 208 Î¼mol//L. Mr. X has retired from the military and is living with his wife, who monitors his medications and compliance. He used to be a chronic smoker but has stopped smoking 15 years ago. His previous medication history is as below:
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Drug and Form
Table 1: Table showing past medications of Mr. X.
Mr. X takes no non-prescription medications and has no known drug allergies.
On examination he appears to be alert and comfortable on his nasal cannula for delivery of oxygen 3L/min. His blood pressure is 134/81 mmHg, pulse rate is 76 bpm, body temperature 37oC, SpO2 of 99%, abdomen feels soft and non-tender, and no pedal oedema was observed. A blood glucose strip test reveals that Mr. X's glucose levels were 10.3 mmol/L. Emergency ECG shows right bundle branch block and no ischaemic changes. The tentative diagnosis was unstable angina and further tests were scheduled, including a full blood count (FBC), renal profile (RP), liver function test (LFT), troponin and creatinine (CKMB) investigations, as well as a urine full examination and microscopy (UFEME). The immediate plan was to give Mr. X subcutaneous enoxaparin 60 mg stat and twice daily thereafter, aspirin 75 mg tablets once daily, lovastatin 20 mg tablets once daily, sublingual glyceryl trinitrate when required, and to continue the 3L/min oxygen cannula.
Patient was well, free from chest pain, tolerating orally and suffering from no nausea or vomiting. He had minimal shortness of breath (SOB). Troponin I levels were at 0.15 ng/mL and ECG showed no acute or evolving changes. Fasting plasma glucose was at 4.8 mmol/L (within normal range). Secondary dehydration was observed using the 'skin pinch' test, so patient was started on intravenous normal saline drip (3 x 500 mL bag per 24 hours). Patient was found to be anaemic due to pre-existing chronic renal failure.
Patient reported mild chest pain and SOB. His troponin I levels were 0.15 ng/mL and other vitals were normal. His creatinine levels were 423 Î¼mol/L.
Patient felt comfortable and his vitals were normal. His creatinine levels decreased to 345 Î¼mol/L.
Patient's condition was well, no chest pain was reported but he was still experiencing some SOB in the morning, which subsided in the afternoon. Patient was put on continuous peritoneal dialysis in the late morning. Patient's vitals were normal, and he was taken off enoxaparin in the evening.
Patient complained of chest pain in the morning, with minimal SOB. His vitals were normal. Subcutaneous enoxaparin 60 mg was given and the IV saline was continued.
Urine Biochemical Analysis (Day 1)
< 2 mm3
Always on Time
Marked to Standard
1.003 - 1.040
4.6 - 8.0
Table 2: Results of urine biochemical analysis on Day 1
Lipid Panel - Fasting Serum Lipid
Plasma total cholesterol / mmol/L
High risk >6.20
Plasma triglyceride / mmol/L
High risk >5.65
Plasma LDL-cholesterol / mmol/L
High risk >4.13
Plasma HDL-cholesterol / mmol/L
High risk <1.03
Total cholesterol / HDL-cholesterol
High risk >5.9
Table 3: Results of lipid panel (fasting serum lipid levels).
Measured levels on Day 1-1.14am
Measured levels on Day 1-12.54am
Measured levels on Day 2-10.47am
Urea / mmol/L
Sodium / mmol/L
Potassium / mmol/L
Chloride / mmol/L
Creatinine / Î¼mol/L
Table 4: Renal profile of Mr. X showing levels of electrolytes and creatinine.
Plasma troponin I - 0.15 ng/mL
Liver Function Test
Plasma total protein
Plasma alkaline phosphatase
Plasma aspartate transaminase
Plasma alanine transaminase
43 u/L â†‘
Plasma total bilirubin
Table 5: Results of liver function test showing protein and liver enzyme levels in plasma.
Full Blood Count (FBC) (Beckman Coulter)
Mean cell volume
Mean cell haemoglobin
Table 6: Full blood count of Mr. X.
Vital Stats Chart
Blood Pressure/ mmHg
Temperature / oC
Pulse Rate/ bpm
Blood Glucose levels/ mmol/L
Table 7: Records of vital stats of Mr. X from Day 0 - 3.
Disease Overview & Pharmacological Basis of Drug Therapy
Acute coronary syndrome (ACS) is a broad term used to classify a continuum of symptoms and events stemming from acute ischaemic episodes affecting the cardiac muscle.1 This includes unstable angina, non-ST segment elevation myocardial infarction (NTEMI), and ST segment elevation infarction. It is usually characterised by chest pain which increases in its severity at rest or with physical exertion. The ischaemic events usually arise from the development of unstable atheromatous plaques,2 which explains the fact that stable angina (due to a stable coronary atheromatous plaque) is not included under this umbrella term. Rupture, ulceration or fissures of the atherosclerotic plaque often leads to formation of a thrombus, causing occlusion of coronary arteries and inadequate blood flow and, subsequently, inadequate supply of oxygen and nutrients to the cardiac muscle. This can be precipitated by acute stress factors on the sclerotic cap usually consisting of fibrous material, which is caused by local blood flow disturbances or vasospasms3. Unstable angina usually occurs without cardiac muscle damage while myocardial infarction (MI) may occur with or without myocardium damage. The thrombus formed in unstable angina is labile and obstruction is transient, and not a full-on occlusion as would occur in MI.4 Unstable angina occurs at rest and is almost indistinguishable from a non-ST segment elevated myocardial infarction except in the severity of cardiac muscle ischaemia. Theoretical definitions of unstable angina would include changes in usual patterns of stable angina after a stable pain-free period, or severe acute anginal pain causing almost total incapacity5, though it is difficult to define it exactly as the term is often used by medical professionals to describe a range of different conditions intermediate between stable angina and MI. The primary clinical symptoms of unstable angina are: sudden occurrence of chest pain that persists for more than 20 minutes which may be felt in other areas such as the jaw, arm, shoulder, neck or back; without cause (as opposed to stable angina which stems from physical exercise); shortness of breath, rapid pulse rate, and sometimes a rapid drop in blood pressure. Patients suffering from an ACS have a high risk of MI and possible even death; immediate hospitalization is often required1 and treatment is of a more urgent nature compared to that of stable angina. It has been suggested by the National Health Service (NHS) Hospital Episode Statistics in 1998 that 1000 out of every million per population is affected with unstable angina, or 10 acute hospital admissions per week.6 On a more recent note, NHS has reported in 2009 that angina affects between 10-15% of women and 10-20% of men aged 65 and above in England.7 Due to the close relationship between unstable angina and coronary events, it is worth noting that the highest averaged rates of cardiovascular events were observed in Glasgow and Belfast (UK), North Karelia and Kuopio (Finland), Newcastle (Australia), and Warsaw (Poland).8
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Diagnosis of an unstable angina episode, or any ACS in that matter, is based on several aspects9. Physical symptoms include anginal pain at rest that lasts for 20 minutes or more; new onset angina severely limiting ability of physical activity; or changes in existing angina intensity, frequency or length of attack. One or more of these symptoms are an urgent indication that the patient is suffering from an ACS attack. Upon admission to hospital, ECG and blood tests should be performed to confirm the type of ACS in order to initiate treatment. In unstable angina, the ST segment is not elevated and levels of cardiac enzymes are normal (especially troponin T and I). If the onset of symptoms is unclear as to indicate ACS, a measurement of serum troponin concentration should be carried out 12 hours from presentation to establish the diagnosis.10 Treatment of unstable angina and NSTEMI are similar in terms of pharmacological management; indeed they are at presentation indistinguishable except in terms of the severity and extent of cardiac muscle ischaemia, in which the ischaemia is less severe in unstable angina and less troponin T and I are released into the bloodstream.
Antiplatelet agents. Aspirin and clopidogrel are the immediate 'emergency' drugs used in the ambulance, both being antiplatelet drugs. Aspirin is an irreversible inhibitor of arachidonate cyclooxygenase (COX) enzyme, in which covalent acetylation of the serine moiety in a hydrophobic channel in the enzyme11 reduces synthesis of thromboxane A2 in platelets and prostaglandins in the endothelium. This prevents platelet aggregation and further enlargement of the thrombus formed in the coronary artery. Clopidogrel is an inhibitor of the ADP-dependent activation of the GPIIb/IIIa receptor and prevents the formation of fibrinogen bridges between glycoprotein IIb/IIIa receptors on the surfaces of platelets11, subsequently preventing platelet activation. Glycoprotein IIB/IIIA receptor antagonists, eg, abxicimab, have the advantage of inhibiting all pathways in the platelet activation process by inhibiting the glycoprotein IIB/IIIA receptor.
Anticoagulants. Unfractionated heparin is an activator of antithrombin III, which inhibits the action of thrombin and serine proteases. The heparin also binds to thrombin; the combined effect of this and the heparin-antithrombin complex formed inhibits thrombin, which decreases the conversion of fibrinogen to fibrin and reduces platelet aggregation. In contrast, low molecular weight heparins (LMWH) have molecular sizes that are too small to bind to thrombin but still bind to antithrombin III, which inactivates all serine proteases including Factors XIIa, IXa, and Xa11, preventing the coagulation process. Direct thrombin inhibitors such as hirudin and bivalirudin inhibit thrombin reversibly. These agents can bind to free and bound thrombin, thus have the ability to prevent and dissolve preformed clots. Synthetic pentasaccharides (fondaparinux) is a selective indirect inhibitor of Factor Xa. It binds to antithrombin III reversibly, catalyzing the inactivation of Factor Xa12 and inhibiting the coagulation cascade.
Beta blockers. All beta blockers bind to beta-adrenoceptors, competitively antagonizing the action of catecholamines. These drugs block the beta-1 adrenoceptors at the heart, achieving a decreased heart rate and force of cardiac contractions, as well as lowering blood pressure. Atenolol is relatively specific for cardiac beta-1 adrenoceptors and exerts fewer side effects associated with beta-2 adrenoceptor blockade, for example bronchospasm in asthmatics.
Nitrates. Organic nitrates mimic the actions of endogenous nitric oxide to relax vascular smooth muscle by increasing the synthesis of cGMP, leading to the dephosphorylation of myosin light chains.11 Vasodilatation of coronary arteries causes increased coronary blood flow and coupled with its effects of decreasing arterial pressure and also cardiac output, the myocardial oxygen consumption is largely reduced.
Statins. Also termed HMG-CoA reductase inhibitors, these medicines inhibit the rate-limiting enzyme in the synthesis of cholesterol, in which this enzyme converts HMG-CoA to mevalonic acid.
ACE inhibitors are diuretics acting on the rennin-angiotensin system which inhibit the angiotensin-converting enzyme (ACE) and block the production of angiotensin II from angiotensin I. This reduces vascular resistance, increases tissue perfusion, and reduces cardiac afterload.
Angiotensin II receptor inhibitors also act on the same system as the ACE inhibitors, except that they block the angiotensin II receptors directly instead of inhibiting their formation. The outcome is the same as above.
Evidence for Treatment of the Condition
The SIGN guidelines advocate that aspirin and clopidogrel be given to patients with ECG ischaemic changes or increased levels of cardiac markers; and aspirin is advocated for all patients suffering from ACS. A meta-analysis of 287 randomised trials proves the protective effect of aspirin on patients with unstable angina, halving the rate of cardiovascular events, including death, non-fatal MI and strokes, or also termed the first primary outcome; while in those with an acute MI, it reduces the rate of coronary events by almost a third13. Long-term use of aspirin for these patients was also shown to be a beneficial antiplatelet therapy. According to the same study, reduction of serious vascular events by clopidogrel was 10% compared to aspirin. The combined use of clopidogrel and aspirin as compared with a placebo and aspirin showed significantly higher success rates in reducing occurrences of first primary outcomes (9.3% compared to 11.4%, P<0.001), as well as the second primary outcome (eg. refractory ischaemia), which occurred in 16.5% of the group given the aspirin-clopidogrel combination, and 18.8% for the placebo-aspirin group14. The patient in context was given only aspirin 75 mg upon admission and once daily thereafter, which are not in accordance with the SIGN guidelines and evidences above which advocate the use of aspirin 300 mg stat and 75-150 mg as long term maintenance therapy. The aforementioned meta-analysis found that a minimum dose of 150 mg aspirin was necessary as an immediate loading dose; doses of 75-150 mg were effective as antiplatelet prophylaxis. The insufficient loading dose appears to put the patient at risk of another ACS event due to inadequate antiplatelet therapeutic doses.
On the flipside, although short term studies have shown that antiplatelet medications are effective for patients with renal failure in the prevention of serious vascular events13, the risks of bleeding is increased by renal disease15, posing a possible contraindication for antiplatelets to Mr. X. A clinical study found that treatment for NSTEMI ACS in patients with chronic renal disease (mild to moderate stages) was less aggressive than those with normal renal function, despite the risk that these patients with renal disease would experience greater adverse outcomes from insufficient treatment for ACS compared to the other patient group16. However the available information on adverse effects of antiplatelets on patients with varying degrees of renal disease is limited and it would appear that this would result in the reluctance of medical professionals in using this class of drugs for patients with chronic renal disease as well as ACS.
It can be inferred that Mr. X would gain the maximum benefits if his medications were changed to aspirin 300 mg and clopidogrel 300 mg stat and aspirin 75 mg and clopidogrel 75 mg thereafter, in which the patient should be closely monitored for signs of bleeding.
Heparins & LMWHs
A 2003 review of 7 studies involving 11,092 patients with non-ST elevation ACS found that low molecular weight heparins (LMWH) were more effective than unfractionated heparins in reducing MI events, requirement for revascularization procedures, and thrombocytopenia17. No difference in the mortality, recurrent angina, major and minor bleeds were observed in the two types of drugs. A meta-analysis of 12 randomised trials with 17,157 patients involved found that patients who have had a non-ST elevation ACS who were put on aspirin experienced no significant difference in benefits in efficacy (preventing MI or death) or safety (major and minor bleeding complications) when they were put on unfractionated heparin or LMWH17, implicating no difference in the thrombolytic effect in both classes of drugs. These results are partially similar to those of the first review. Another meta-analysis of 2 phase-3 trials comparing enoxaparin and unfractionated heparin, on the other hand, showed a significant (20%) difference in reducing death or severe cardiac ischaemic events18. From an economic point of view, authors of yet another meta-analysis on the subject stated that the cost of LMWH is 3-5 times higher than unfractionated heparin19. From these data it can be concluded that LMWHs does indeed have additional positive treatment outcomes compared to unfractionated heparins22; it does not show significantly decreased side effects (bleeding).
Enoxaparin has, though, an increased bleeding effect on patients with renal disease as reported by an investigation of 106 patients, in which total bleeding complications occurred in 22% of normal patients and 51% of patients with impaired renal function (p<0.01). A significant difference was also found in incidences of major bleeding and increased use of blood products in the latter group of patients20. In a study that involves patients with unstable angina excluded from the ESSENCE and TIMI-11B trials (including patients with creatinine clearance <30mL/min), it was found that enoxaparin provided levels of sufficient anti-factor Xa, and when the dose was adjusted to creatinine clearance, no excess bleeding occurred21. This shows that enoxaparin can still be used safely in patients with chronic renal disease as long as the dose of enoxaparin and the patient's condition are closely monitored.
It is still the drug of choice for patients present with non-ST elevated ACS, and this is applicable to Mr. X with unstable angina.
Beta-blockers were not prescribed for Mr. X. The SIGN guidelines states that beta-blockers should be the drug of choice for first line treatment of anginal pain in patients with non-ST elevated ACS. A meta-analysis of 5 trials consisting of 4700 patients in all showed a 13% reduction in anginal pain with the use of beta blockers (initially IV then oral for a week) in patients with non-ST elevated, MI-characterised chest pain23. It was stated in the clinical progress Mr. X had chest pain on Day 1 and 4, thus the addition of a beta blocker to his medications would be useful in alleviating his pain. Despite the popular belief that beta-blockers are contraindicated in patients with diabetes mellitus, it is possible to treat these patients using beta-blockers as long as good glycaemic control is achieved and the patient is monitored regularly24. This would further support its use in Mr. X; furthermore, several studies have shown that diabetic patients derive a significant benefit from the use of beta-blockers after an MI, in which diabetic patients had a significantly lower mortality 1 year post-discharge25, total mortality after 3 years, and deaths from cardiac events26. A multicentre randomized trial, the HINT trial, on patients with unstable angina found that metoprolol, a relatively cardioselective beta blocker, reduced occurrence of myocardial ischaemia or progress to MI within 48 hours, indicating that metoprolol has a short term beneficial effect on patients not already taking beta blockers prior to the unstable angina episode27. It has been suggested that beta-blockers be the first line treatment for unstable angina and if patients remain unstable, a calcium channel blocker should be added28.
The beneficial effects of statins in reducing mortality and cardiovascular events have been proven by a meta-analysis of large, randomized controlled trials (n=90,056) where coronary artery disease was present or absent29. The positive results were also proven spanning a large range of serum cholesterol levels. Investigations comparing the use of intensive versus moderate doses of statins in the early stages and post-ACS showed positive results: a meta-analysis of 4 large trials (n=27,548) shows a 16% reduction in cardiovascular deaths or MI, as well as a 16% reduction in cardiovascular deaths or coronary events30. This view is shared by another meta-analysis of the same subject of 13 randomised controlled trials which found a decrease in mortality and coronary events after 4 months of treatment31. These data support the use of statins by Mr. X.
Nitrates have been widely used in relieving pain from unstable angina, despite its lack of clinical evidence in supporting its role in improving survival and reducing the rate of MI and cardiovascular events32. ISIS-433 and GISSI-334 reports no significant difference of the use of glyceryl trinitrate post-MI in reducing the overall mortality; however this may be explained by the fact that more than 50% of patients in the controlled group are also on other forms of nitrate therapy, such as intravenous glyceryl trinitrate. Despite this, nitrates will still be of use for reducing the pain in post-MI patients and those with unstable angina. The BNF advises against the use of nitrates in patients with serious anaemia (Hb<75g/L) but as Mr. X's haemoglobin levels are well above this level and he was undergoing therapy to correct his anaemia, nitrates can be quite safely used for his case, although it would be wise to use them as-required instead of prophylactically.
Mr. X's plasma glucose levels were elevated on the day he was admitted to hospital (13.9 mmol/L). Diabetes mellitus has been proven to be a strong independent risk marker for coronary heart disease: patients with poorly controlled diabetes at hospital admission have a worse outlook on prognosis and future development of cardiovascular events35. The DIGAMI investigation reports that the use of intensive insulin therapy increased long-term prognosis (P=0.011) of patients presenting with hyperglycemia (>11mmol/L) at admission compared with those on standard antidiabetic therapy36. These data support the use of insulin to control the blood glucose levels of Mr. X which were highly increased upon admission. This is also supported by the SIGN guidelines which advocate immediate control of blood glucose is carried out for MI patients with glucose levels of more than 11.0 mmol/L for at least 24 hours.
The SIGN guidelines recommend that patients with unstable angina should be given ACE inhibitors as long-term therapy. In patients at high risk of cardiovascular events, ACE inhibitors (ramipril was investigated in a report37) have been proven to reduce overall mortality, MI, and stroke, particularly in patients with diabetes mellitus. Perindopril was found to reduce cardiovascular risk (relative risk reduction =20%, P=0.0003) in a population with stable coronary heart disease in absence of heart failure38 in a double-blinded, randomized multicentre trial involving 13,655 patients. A meta-analysis of the 2 above trials and a third one (PEACE) showed a reduction in overall mortality, cardiovascular death, non-fatal myocardial infarction, stroke, heart failure, and coronary artery bypass surgery by ACE inhibitors39. This demonstrates the benefits of ACE inhibitors in patients with atherosclerosis: as patients who had an ACS event would have a higher rate of cardiovascular events, the positive outcomes of ACE inhibitors can perhaps be extrapolated to this population in order to decrease coronary events and improve prognosis. However, the BNF advises caution and close clinical monitoring if ACE inhibitors are to be used in patients with hyponatremia (<130 mmol/L as is the case with Mr. X): the side-effects of ACE inhibitors including hyperkalemia are more common in patients with decreased renal function. These data can be extrapolated to explain that ACE inhibitors can be used for Mr. X in lieu of their many positive outcomes, with the condition that his electrolyte levels are monitored regularly.
On admission, Mr. X's SpO2 was 99% and remained high throughout his stay in the hospital. The use of oxygen therapy is significantly beneficial only in hypoxic patients (with SpO2 <90%), pulmonary oedema or MI which is continuing in nature40. Administration of oxygen therapy to patients with ACS has not been proven to be of significant benefit in improving clinical outcomes or in the reduction in the size of infarction41.
Anaemia and Unstable Angina
Anaemia can disturb the balance between myocardial oxygen supply and demand: a decrease in the number of red blood cells can lead to a reduction in the supply of oxygen to the myocardium. Thus correction of the causative factor would be sensible in the treatment of unstable angina for the patient in context. Mr. X was given a combination of ferrous fumarate, vitamin B complex, and folic acid for treatment of his anaemia. From the data in Table 6, it can be seen that Mr. X has low haemoglobin concentrations (95 g/L) and a low mean cell volume (81.8 fl.). To confirm that Mr. X is indeed suffering from iron-deficiency anaemia (as suggested by his treatment medication), three parameters must be established namely the plasma iron, the plasma ferritin, and total iron binding capacity. However, as very few conditions can cause abnormalities in the mean cell volume, and a decreased value is due to iron-deficiency anaemia or thalassemia42, it is safe to assume that Mr. X's anaemic condition is due to an insufficiency of iron. Iron supplements are given to correct the iron status of the patient, in which the ferrous form given orally is found to be cheap, safe and effective in the majority of patients with iron-deficiency anaemia2. Vitamin B complex and folic acid are only indicated in patients with the respective deficiencies2; there is little evidence that they would be of any significant benefit in patients with iron-deficiency anaemia.
Based on the evidence given, Mr. X's aspirin dose should be changed to 300 mg stat and 75 mg thereafter, and clopidogrel should be added into his medication profile in the same doses. These changes ensure that Mr. X is obtaining sufficient antiplatelet effects from his medications to prevent another attack of unstable angina or even a myocardial infarction. Present drugs that were given for his condition that are suitable and supported by evidences include enoxaparin, lovastatin, insulin, and GTN: these can be safely continued without problems. A beta-blocker (metoprolol tablets) may be given additionally in doses of 50-100 mg as evidences described above have shown that they can be safely used in diabetic patients contrary to popular belief; an ACE inhibitor (perindopril as previously used by Mr. X) may be initiated coupled with regular electrolyte monitoring for his condition. Oxygen therapy was probably not required as shown by the aforementioned reports. All in all, the pharmacological therapy for Mr. X should be tailored to his specific conditions (unstable angina, chronic renal disease, anaemia) and although his current medication profile is adequate, a few changes can be made to improve clinical outcome and decrease his probability of suffering from another acute coronary event.