SA, with body mass index 19.1 kg/m2 (body weight= 46kg, body height= 1.55m), is a 50 year-old Malay female who admitted into the hospital under the companion of her daughter after she complaint about the pain on her chest, dizziness and shortness of breath. She claimed that she experienced the chest pain for the past 7 days when she felt 'surprised', 1 to 2 episodes per day and every episode lasted for around 30 minutes. According to her daughter, SA is a housewife and she had no known drugs allergies. In addition, SA is a non-smoker and she had no alcoholic-drinking habit. There was no any significant medical history in her family. Based on her medical records, she has been suffering from hypertension and type II diabetes mellitus for the last 10 years. Some relevant drug histories are stated in the table 1.
Table 1 Relevant drug history of SA
Dose and Frequency
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40mg 3 times daily
75mg once daily
500mg 3 times daily
5mg twice daily
During examination, SA was alert and conscious. She was afebrile (body temperature = 37oC) but her blood pressure and pulse rate were elevated, i.e. 165/77mmHg and 100bpm respectively as well as her blood glucose level (12.8mmol/L). There was no detection of abnormality on her abdominal system (i.e. soft and non-tender) and respiratory system (i.e. lung was clear). Besides, cardiovascular system presented as dual resonance non-murmur upon examination. According to her, the chest pain was occurred on exertion, and it was pressing in nature, localised restrosternal and non-radiating. She experienced palpitation which associated with giddiness. However, she was not suffering from profuse sweating, tremor, nausea and vomiting.
According to the electrocardiogram (ECG), cardiac profile of the patient revealed non-ST segment elevation (with ST-segment depression). Besides, the biochemical cardiac marker test shown that the value of troponin I was in the normal range (0.03ng/mL). This was to rule out the possibility of myocardial infarction as there was no cardiac enzyme detected in the bloodstream. As a result, SA was newly diagnosed with unstable angina, together with previous diagnosed hypertension and type II diabetes mellitus.
Laboratory investigations on SA's renal profile, liver profile, blood profile and serum lipid profile were done on first day of admission. The renal profile of SA was generally good with normal calculated creatinine clearance, 78.3ml/min (normal range: 78-120ml/min). However, the level of potassium and urea was slightly lower than normal range. Besides, the liver function test indicated that her liver function was reasonably acceptable, except the low level of plasma albumin, which may result in hypoalbuminemia. In addition, the blood profile shown that SA may suffer from anaemia as haemoglobin, mean cell volume and haematocrit were at the level lower than normal range. Last but not least, the fasting serum lipid profile indicated that SA was at high of hypercholesterolemia as the level of HDL-cholesterol was lower than desired range and the level of triglyceride and the ratio of total cholesterol to HDL-cholesterol was higher than desired range. All the abnormal results of laboratory test were stated in Table 2.
Table 2 The abnormal results of laboratory investigation of SA on first day of hospital admission.
Result on day 1
Result on day 1
Ratio of albumin to globulin (25-44 g/L)
Result on Day 1
Fasting serum lipid profile
Result on Day 1
Desirable < 1.7 mmol/L
Borderline 1.7-5.84 mmol/L
High Risk > 5.84 mmol/L
Mean cell volume
Desirable > 1.29 mmol/L
High Risk < 1.29 mmol/L
Always on Time
Marked to Standard
Total Cholesterol/ HDL-Cholesterol
Desirable < 3.8
High Risk > 5.8
After examination and diagnosis, a therapeutic management plan was prepared for SA. In this plan, aspirin tablet (300mg immediately and 75mg once daily thereafter) was given to SA as an antiplatelet agent whereas enoxaparin (60mg immediately and 60mg twice daily thereafter) was given subcutaneously as an anticoagulant agent. Besides, SA was also given with metoprolol tablet (25mg immediately and 50mg twice daily thereafter) as an antihypertensive agent. In addition, she was also on simvastatin tablet (20mg once daily) for restoration of normal lipid profile and for secondary prevention of cardiovascular events. Moreover, for management of type II diabetes mellitus, SA was commenced on 8 Ü of soluble insulin 100Ü/ml (Humulin R) subcutaneously as an acute management while metformin tablet (500mg three times daily), glibenclamide tablet (5mg twice daily) and Humulin R (8 Ü three times daily) as maintenance treatment for type II diabetes mellitus.
On second day of admission, the conditions of SA were improved. She did not experience any chest pain, palpitation or shortness of breath throughout the night. However, she was suffered from epigastric pain in the evening. After examination, it was confirmed that the epigastric pain was resulted from unstable angina, as the pain was radiating to other parts of the body. Thus, sublingual glyceryl trinitrate (GTN) tablet (0.5mg immediately and 0.5mg when required) was given to SA to relieve the pain. All the medications prescribed on the previous day were continued as usual.
Clinical examination of SA on third day of admission showed that her conditions were generally well. No chest pain was observed. However, her blood pressure was high (160/90 mmHg) in the morning. Thus, perindopril tablet (4mg once daily) was given to SA as an additional antihypertensive agent. Besides, SA was also experienced hypoglycaemia in the afternoon with blood glucose level of 3.2mmol/L. As a result, insulin therapy was withdrawn while the long acting oral sulphonylurea, glibenclamide was replaced by shorter-acting oral sulphonylurea, gliclazide tablet (80mg twice daily) in order to restore the blood glucose level back to the normal range. It should be noted that the simvastatin therapy was also stopped on that day.
The conditions of SA on fourth day of admission were generally well. Her blood pressure and blood glucose level were normal. The medications were continued as usual. ECG investigation was planned for SA for further examination on her cardiac function. SA was keep in view for discharged. As a whole, the condition of unstable angina of SA was under controlled throughout the stay in hospital but her blood pressure and blood glucose levels were fluctuating throughout the period of hospital admission, as shown in Figure 1 and Figure 2 respectively.
Figure 1 Blood pressure profile of SA during hospital admission.
Figure 2 Random blood glucose profile of SA during hospital admission.
Table 3 Drug chart for SA during her hospital admission. UA: unstable angina; Htn: hypertension; LLA: lipid lowering agent; DM II: type II diabetes mellitus.
Drug & Route
Dose & Frequency
60mg stat, then 60mg bd
300mg stat, then 75mg od
25mg stat, then 50mg bd
S/C Humulin R -Regular Human Insulin
(100 Ü /ml)
8 Ü tds
S/L Glyceryl Trinitrate
0.5mg stat, then 0.5mg prn
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2. Disease Overview and Pharmacological Basis of Drug Therapy
Acute coronary syndromes (ACS) can be described as clinical syndromes that result from acute obstruction of a coronary artery which gives rise to a condition of acute myocardial ischemia.1 This ischemic state is caused by an imbalance between oxygen supply and demand in myocardial tissues following the obstruction of coronary artery and it may lead to necrosis of myocardial tissues.2 Classification of ACS is illustrated in Figure 3.1
Figure 3 Classification of acute coronary syndrome.1
Acute Coronary Syndrome
ST Elevation Myocardial Infarction (STEMI)
Non-ST Elevation Myocardial Infarction (NSTEMI)
Unstable angina: Incidences, Diagnosis, Pathophysiology
According to Peters and his colleagues, there are about 114000 patients per annum in United Kingdom admitted to hospital because of acute coronary syndromes.3 Based on NHS hospital episode statistics, it was suggested that the incidence of unstable angina is around 90000 cases per year in England and Wales.4 The number of cases of unstable angina is rising each year with prevalence in men than women.
Although UA and NSTEMI are classified under the same class as non ST-segment elevation ACS but they are still distinguishable as NSTEMI induces the release of biochemical cardiac markers like creatinine kinase-MB, troponin I or troponin T following myocardial necrosis which resulted from severe ischemic state into the bloodstream whereas there is no release of these biomarkers in UA.5 Differentiation between NSTEMI and UA can be achieved by detecting the presence of these biomarkers in the bloodstream, normally within six hours, after the onset of chest pain,.5,6 Hence, the diagnosis of UA is based upon the electrocardiographic (ECG) findings (no changes or ST-segment depression) to rule out the possibility of ST-segment elevation ACS (STEMI) and the absence of biomarkers in the bloodstream to exclude the presence of NSTEMI. In addition, a careful review for signs and symptoms of UA and physical examinations are also required to aid diagnosis.7
The most common presenting symptom of UA is chest pain but there are also other symptoms including shortness of breath, arm pain, fatigue, dyspnoea, palpitation or profuse sweating.5 However, some episodes of UA may present without chest pain, especially in diabetic and elderly patient.8
The underlying pathophysiologic cause of UA is the formation of thrombus that developed on a ruptured vulnerable atheromatous plaque at coronary vessel wall.5 Generally, the vulnerable plaque (as shown in Figure 4) in UA is composed of a large lipid-rich core and covered by a thin fibrous cap. The thinning and breakdown of the fibrous cap leads to the instability and rupture of the plaque. The fissuring of the plaque induces platelet aggregation and activates the coagulating pathway.2,9 As a consequence, thrombus is formed at vessel wall. Thus, the partial occlusion of coronary artery by thrombus gives rise to unstable angina with interruptions of blood perfusion between myocardial tissues.2,9
Figure 4 Characteristics of stable, unstable and ruptured atherosclerotic plaque.10
2.2 Pharmacological basis of drug therapy
The aims of pharmacological management of UA are to relieve chest pain, to prevent fully occlusion of coronary artery and hence to increase survival and reduce morbidity and mortality. Drug therapies that utilised in the management of UA include antiplatelet therapy, anticoagulant therapy, anti-ischemic therapy, lipid-lowering therapy and angiotensin-converting enzyme inhibitors.
2.2.1 Antiplatelet Therapy: Aspirin
Antiplatelet therapy should be started immediately after diagnosis of UA. The drug of choice is aspirin. A thienopyridine should be given for patients who are intolerant with aspirin or at high risk of developing cardiovascular events.4 Platetlet glycoprotein IIb/IIIa receptor inhibitors should be administered in combination with other antiplatelet therapies to reduce mortality.5 The role of different antiplatelet agents are shown in Figure 5.
Aspirin inhibits cyclooxygenase-1 enzyme which is useful in catalysing the conversion of arachidonic acid to cyclic endoperoxides such as prostaglandins. This in turn inhibits the formation of thromboxane A2 and therefore reduces platelet aggregation and inflammation.11,12 Thus, it reduces the risk of thrombosis in UA.
Aspirin Platelet agonists
Ticlopidine Thromboxane A2 ADP
Tirofiban Activation of GP IIb/IIIa
Figure 5 Role of antiplatelet agents in inhibiting formation of thrombus.4,5
2.2.2 Anticoagulant Therapy: Enoxaparin
The short-term use of parenteral heparin as an anticoagulant agent, either unfractionated heparin (UFH) or low molecular weight heparin (LMWH), is crucial in managing the thrombotic events of UA.5 Enoxaparin inhibits the coagulation pathways by inducing conformational changes of antithrombin III. The activated antithrombin III catalyses the inhibition of Xa factor which in turn hinders the conversion of prothrombin to thrombin and hence disrupts the blood clotting pathways, as shown in Figure 6.13,14
Figure 6 The role of LMWH and UFH in the coagulation pathway to prevent fibrin formation.14
2.2.3 Anti-ischemic Therapy: Metoprolol & Glyceryl Trinitrate
Anti-ischemic agents, such as beta-blockers, nitrates and calcium channel blockers, are efficient in restoring myocardial balance by either increasing oxygen supply or reducing oxygen demand of myocardial tissues.5
Metoprolol inhibits the activity of circulating catecholamines on beta-adrenoceptors. This contributes to a reduction in cardiac contractility and heart rate which in turn decreases myocardial oxygen demand. Thus, the myocardial oxygen balance can be restored. As a result, patients with UA are benefit from symptomatic relief and prevention of further ischemic events.11,15
Glyceryl trinitrate(GTN) could be metabolised to organic nitrate that could release nitrate oxide.12 Nitrate oxide induces the formation of cyclic GMP that activates cGMP-dependent protein kinase.12 This kinase reduces the intracellular calcium concentration and leads to relaxation of vascular smooth muscle.12,16 The dilation of coronary vessels and peripheral veins increases myocardial oxygen supply and reduces myocardial oxygen demand respectively. These contribute to the restoration of oxygen balance at site of ischemia.
2.2.4 Lipid-lowering Therapy: Simvastatin
The statin therapy should be initiated immediately after the onset of UA and maintained on a long-term basis to reduce the rate of recurrence and rate of mortality.11 Simvastatin reduces the concentration of plasma LDL-cholesterol by inhibiting activity of the HMG-CoA reductase in the biosynthesis pathway of cholesterol and hence reduces the risk of UA.12 Besides, it is also useful in stabilizing vulnerable atheromatous plaque in UA with its lipid lowering and pleiotropic effects, as shown in Figure 7.17,18 Consequently, UA, which occurred following thrombotic events that resulted from the rupture of plaque, can be prevented.18
â†“ HMG-CoA reductase
â†“ Mevalonic acid
â†“ Geranyl pyrophosphate
â†“ Farnesyl pyrophosphate
â†“ Geranygeranyl pyrophosphate
â†“ Isoprenylated proteins
â†“ VLDL assembly
â†“ cholesterol- LDL
Lipid-lowering Effects Pleiotropic Effects
Figure 7 The inhibitory role of statin in cholesterol biosynthesis, as well as its lipid-lowering and pleiotropic effects. HMG-CoA= 3-hydroxy-3-methylglutaryl coenzyme-A; SREBP2= sterol-responsive element-binding protein 2; LDL= low density lipoprotein; TG= triglyceride; VLDL= very low density lipoprotein.17
2.2.5 Angiotensin-converting enzyme inhibitor: Perindopril
ACE inhibitors, such as perindopril or enalapril, should be given to patients with UA as a long-term management, especially for those who associated with hypertension, diabetes mellitus, heart failure or left ventricle dysfunction. In the case of intolerant to ACE inhibitors, angiotensin receptor blockers (ARB) like losartan or candesartan should be given to the patients.2,5 Perindopril prevent formation of angiotensin II by inhibiting angiotensin-converting enzyme in renin-angiotensin system. This inactivates angiotensin II-mediated AT1 receptors and hence reduces the release of adrenal aldosterone and increases vasodilatation effects, as in Figure 8.2,12,19 Both of these contribute to the controlling of blood pressure and the long-term benefits of cardioprotective effects.2,12
Figure 8 The inhibitory action of renin inhibitors, ACE (angiotensin-converting enzyme) inhibitors and ARB (angiotensin receptor blockers) in renin-angiotensin system.19
3. Evidence-Based Pharmacological Treatment
3.1 Antiplatelet Therapy
There are several clinical trials conducted to support the clinical benefits of aspirin in management of patients with UA. According to Veterans Administration Cooperative study, 1266 patients were recruited in a randomised-controlled trial (RCT). Daily dose of 324mg aspirin and placebo was given to a group of 625 patients and 641 patients respectively. It was found that the composite risk of death or non-fatal myocardial infarction (non-fatal MI) in aspirin-treating group was 51% (p=0.0005) lower than placebo group after three-month follow-up.20
Besides, 479 patients with UA were included in a study conducted by the Montreal Heart Institute. They received therapy of aspirin, heparin, both aspirin and heparin or placebo after hospital admission for at least 6 days. The incidences of MI were reduced (71% reduction) in the group of patients who treated with aspirin, with 3% of them (p=0.01) suffered from MI compared to 12% of patients in placebo group.21 In addition, according to the Research Group on Instability in Coronary Artery Disease in Southeast Sweden (RISC), 796 patients with UA or non-Q-wave MI who randomly assigned to receive 75mg aspirin daily gained benefit from a risk reduction of 57-69% in experiencing MI or cardiovascular death after treatment if compared to the placebo group.22
These established documentations have led to the recommendation of use of aspirin in the management of patients with non-ST elevation ACS or acute MI as part of the primary or secondary preventive management. In relation to case summary, aspirin was recommended and given to SA as a secondary preventive measure in UA. Besides, a meta-analysis of Antithrombotic Trialists' Collaboration which involved 287 studies (135000 patients with high risk of occlusive vascular events) suggested that treatment with high dose aspirin (initial loading dose of 150-300mg) is necessary in acute management while low dose aspirin (daily dose of 75-150mg) is needed in long-term management.23 The dosage regime of aspirin (300mg immediately, followed by 75mg daily) for SA is justified.
The concurrent use of aspirin and clopidogrel has been proved to be more effective than the use of aspirin alone in reducing the risk of recurrent events of non-ST segment elevation ACS like UA. In a RCT conducted by Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) investigators, 12562 patients who had presented chest pain within 24 hours after the onset of symptoms were involved.24 6259 of them were given with aspirin (75-325mg daily) together with clopidogrel (an immediate loading dose of 300mg followed by 75mg daily) while 6303 of them were given with aspirin (75-325mg daily) and matching placebo as a controlled group for a duration of 3 to 12 months. According to the analysis, therapeutic effects of the dual antiplatelets therapy were superior to that of aspirin-placebo-therapy as the combination therapy showed a more significant reduction in the risk of ischemic stroke, non-fatal MI, cardiovascular events or refractory ischemia if compared to aspirin-placebo-therapy (25.8% and 30.2% respectively with p<0.001).24 Thus, the combination therapy should be recommended instead of aspirin monotherapy. However, there was only aspirin being prescribed for SA. This is because SA was at a low risk of developing cardiovascular events (according to TIMI risk assessment), thus aspirin monotherapy was sufficient to control her conditions.5
3.2 Anticoagulant Therapy
According to ACC/AHA guideline, the use of combined therapy of antiplatelet (aspirin) and anticoagulant (heparin) have exerted better beneficial effects in managing thrombotic events and reducing rate of death or MI in patients with UA if compared to aspirin monotherapy.5 Based on a study designed by Gurfinkel and his colleagues, the combined therapy of aspirin and LMWH (G3) was superior to either aspirin monotherapy (G1) or combined therapy of aspirin and UFH (G2) in reducing incidences of recurrent angina (21% in G3 compared with 37% in G1 and 44% in G2), non-fatal MI (none in G3 compared with 7 and 4 patients in G1 and G2 respectively) or silent myocardial ischemia (25% in G3 while 38% and 41% in G1 and G2 respectively).25 A conclusion that could be drawn from this study is the management of UA with combination of aspirin and LMWH was significantly more beneficial than treatment with aspirin alone or combination of aspirin and UFH. Thus, the combined therapy of aspirin and enoxaparin for SA is justified.
Besides, it also suggested that the use of LMWH was better than UFH. The superiority of LMWH over UFH was demonstrated in the ESSENCE trial (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events).26 3171 patients were randomised to receive subcutaneous enoxaparin (1 mg/kg 12hourly) or intravenous UFH (5000 units adjusted according to aPTT) together with aspirin (100-325mg daily) throughout the treatment period of 2-8 days.26 The outcome of this trial supported that there was a lower risk of death from cardiovascular causes, recurrent angina or MI in patients with UA/NSTEMI who treated with combined therapy of aspirin and enoxaparin compared to those of having combined therapy of aspirin and UFH after 14 days of observation (16.6% and 19.8% for enoxaparin and UFH respectively, p=0.019).27 The reduction of risk was still noticeable after 30 days of abservation (19.8% vs 23.3%, p=0.016) and after one-year follow-up (32% vs 35.7%, p=0.022).26,27 The results of ESSENCE trial after 12-month follow-up were illustrated in the Figure 9.26
Figure 9 The incidences of the primary composite end point (cardiovascular death, myocardial infarction or recurrent angina) and secondary composite end point (cardiovascular death or myocardial infarction) of the ESSENCE trial after 12-month follow-up.26
In addition, a review report of the Cochrane Library supported that the use of LMWH is more favourable than UFH.28 Fewer cases of thrombocytopenia developed in patients treated with LMWH (1%) as compared to patients who received UFH (1.8%).28 This implied the safer use of LMWH in patients. In case summary, SA was prescribed with enoxaprin, in addition to aspirin therapy. It was indeed appropriate as this combination of treatment offered better therapeutic effects and lesser adverse events.
3.3 Anti-ischemic Therapy
The evidence-based study regarding the recommended use of beta-blockers in patients with UA is limited. Advantages of clinical use of most beta-blockers in UA management were deduced from the analysis of RCTs in patients with STEMI, NSTEMI or stable angina.5 In an overview of results of RCTs done by Yusuf et al., it was claimed that the risk of progression of UA to acute MI was reduced by 13% with the administration of beta-blockers in patients (29% in group with beta blockers versus 32% in group with placebo, p<0.04).29,30
Besides, as shown by HINT (Holland Interuniversity Nifedipine/Metoprolol Trial) study, patients who were not pre-treated with beta-blockers, the relative risk [RR] for nifedipine =1.15 (95%CI:0.83-1.64), for metoprolol =0.76 (95%CI:0.49-1.16) and for the combination of both of these drugs =0.80 (95%CI:0.53- 1.19).31 These results indicated that metoprolol was useful in reducing the risk of developing ischemic recurrence or acute MI from UA whereas the use of nifedipine was not effective. Moreover, the combination of metoprolol and nifedipine exhibited the similar extent of beneficial effects as metoprolol monotherapy in risk reduction.31 On the other hand, the addition of nifedipine therapy to patients who pre-treated with beta-blockers was beneficial in limiting the occurrence of MI progression or ischemic recurrence with RR =0.68 (95%CI:0.47-0.97).31 In short, the addition of nifedipine to patient who pre-treated with beta-blockers was recommended. In case summary, SA was previously prescribed with propanolol before hospital admission. Thus, combined therapy of calcium channel blocker (CCB) and beta-blocker should be recommended for SA. However, there was only metoprolol being administered to SA during admission. This was because, according to ACC/AHA practice guideline, CCB should only be added to the treatment when patient is contraindicated to beta-blocker or unresponsive to beta-blocker.11 In this case, the use of metoprolol is justified as SA is response well to it.
Most studies regarding the benefits of nitrates in relieving anginal symptoms in patients with UA are small and uncontrolled.5 There was a double-blind placebo-controlled study, which recruited 162 patients, suggested that the use of GTN was beneficial in reducing the frequency and duration of chest pain in patients over 48 hours (18% with GTN versus 36% with placebo; RR=0.50, 95%CI:0.25-0.90).32 In another study, 200 patients with UA were involved and randomly receiving GTN, heparin, placebo or combined therapy of GTN and heparin after coronary artery angioplasty.33 The results showed that GTN monotherapy and combined therapy significantly reduce the occurrence of recurrent angina in patients while heparin monotherapy and placebo produced little benefits in a similar context (RR of 43% with GTN; 42% with GTN and heparin; 75% with heparin; 75% with placebo, p<0.002).33
Besides, results from an overview of ten RCTs that involved a total of 2000 patients showed that the risk of cardiovascular mortality in patient with acute MI was reduced by 35% (p<0.001; 95%CI:0.17-0.50) with the administration of nitroglycerin or nitroprusside.34 Another review study reported that nitroglycerin contributed to a mortality reduction of 48% in 850 patients with acute MI (p<0.001; 95%CI:0.25-0.64).35 In addition, the use of nitrate in acute setting decreased the rate of mortality among 58050 patients with acute MI on first day of hospital admission, was shown in the ISSI-4 trial.36
In spite of a paucity of evidences regarding the use of nitrate in management of patients with UA, the use of sublingual GTN in SA is still justifiable because it relieves anginal symptoms in acute management. However, the GTN therapy should be started on first day of admission instead of second day as SA experienced chest pain on admission.
3.4 Lipid-Lowering Therapy
The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study was designed to investigate the effects of statin therapy on recurrent ischemia in UA and NSTEMI.37 There were 3086 patients with UA or NSTEMI recruited in this study and they were randomly given with immediate statin therapy (80mg per day) or matching placebo. After 16-week follow-up, it was noted that there was a lower risk of cardiovascular death, non-fatal MI or recurrent ischemic events in patients with statin therapy (14.8%) if compared to the placebo group (17.4%) with RR=0.84 (95%CI:0.70-1.00; p= 0.048).37,38 These data proposed that early statin therapy can reduce recurrent ischemic events in patients with UA.
The beneficial effects of statin can be further demonstrated in the following clinical trials. According to the Scandinavian Simvastatin Survival Study (4S), it found that long-term lipid lowering effects of simvastatin were useful in delaying progression of coronary artery disease as there were 37% risk reduction (p<0.00001) for acute MI and 22% risk reduction for prolonged anginal pain.39,40 As a result, it can be concluded that simvastatin has contributed to the reduced morbidity and mortality in patients with coronary artery disease. These findings were consistently parallel with the results obtained in meta-analysis that conducted by Gould et al, which emphasized that long-term lipid lowering was significantly associated with the reduced rate of coronary artery disease-related morbidity and mortality in patients.41
Based on a meta-analysis of 13 RCTs performed by Hulton et al., it revealed that the early, intensive statin therapy gave therapeutic benefits in patients with ACS 4 months after the initiation of treatment over a 24-month follow-up period. The survival curves showed that the beneficial effects of statin started to be significant between 4 and 12 months in Figure 10.42
Figure 10 The survival curves demonstrated the benefits of statin in reducing risk of cardiovascular events and ischemic events over 24-month follow-up, with major cardiovascular events (odd ratio [OD]=0.84, 95%CI: 0.76-0.94), ischemia (UA or revascularization) (OD=0.68, 95%CI: 0.50-0.92); myocardial infarction (OD=0.89, 95%CI: 0.60-1.33) and cardiovascular death (OD=0.76, 95%CI:0.66-0.87).42
In addition, the favourable use of early intensive statin therapy also evidenced in the study carried out by de Lemos et al.43 Based on the results, over 2-year observations, an early initiation of aggressive simvastatin therapy (40mg daily for one month, 80mg daily thereafter) offered larger reduction in the risk of cardiovascular events if compared with delayed initiation of less aggressive simvastatin regimen (placebo for four months, 20mg daily thereafter) in patients with ACS (OR=0.75, 95%CI:0.60-0.95, p=0.02).43
According to the studies described in the above, the discontinuation of simvastatin therapy in SA during hospital admission was not appropriate. An early and long-term treatment of statin should be recommended. In addition, the dose of simvastatin should be increased from 20mg to 40mg (up to maximum of 80mg) in order to effectively prevent cardiovascular events.
3.5 Angiotensin-Converting Enzyme Inhibitor
The Heart Outcomes Prevention Evaluation (HOPE) trial was designed to evaluate the long-term use of ACE inhibitors in patients with coronary artery disease, without heart failure or left ventricle dysfunction.44 There were 9297 patients recruited in this study and followed up for an average period of five years. 4645 patients were randomly directed to accept treatment with ACE inhibitor while 4652 patients were given with placebo treatment. Patient group with ACE inhibitor showed significant reduction in rate of cardiovascular mortality (6.1%versus8.1% in patient group with placebo; RR=0.74, 95%CI:0.70-0.86, p<0.001), stroke (3.4%versus4.9%; RR=0.68, 95%CI:0.56-0.84, p<0.001) and MI (9.9% versus 12.3%; RR=0.80, 95%CI:0.70-0.90, p<0.001) if compared to patient group with placebo treatment.44 In short, the relative risk of composite outcome of cardiovascular death, stroke and MI in patient group with ACE inhibitor as compared with the placebo group was 0.78 (95%CI: 0.70-0.86, p<0.001).44
Figure 11 Proportion of patients in the ramipril Group and the placebo Group that associated with myocardial infarction, stroke or cardiovascular death over five-year follow-up in the study.48
In addition, according to clinical review of Acute Infarction Ramipril Efficacy (AIRE), Trandolapril Cardiac Evaluation Study (TRACE), Studies of Left Ventricular Dysfunction (SOLVD) and Survival and Ventricular Enlargement Trial (SAVE), long-term therapy of ACE inhibitors exhibited a significant reduction (23%) in the risk of developing MI in patients with coronary heart disease and left ventricular dysfunction.45 As a result, the use of perindopril in management of UA for SA in a long-term basis to reduce the chance of developing cardiovascular events is justified.
As a summary, the medications (aspirin, enoxaparin, metoprolol and simvastatin) received by SA during acute phase of UA are evidence-based. The use of sublingual GTN as required to relieve anginal pain is also evidence-based. In addition, the long-term therapeutic management of SA as a secondary prevention of cardiovascular events, including the use of aspirin, metoprolol, perindopril and sublingual GTN are based on the evidences from clinical trials. The application of these evidence-based pharmacological interventions in management of SA has improved the medical condition of SA. However, the discontinuation of simvastatin therapy on third day of hospital admission and the administration of an overdose of enoxaparin has been preventing SA from getting a complete and optimal evidence-based therapeutic management as evidence suggested long-term statin treatment is essential in reducing morbidity and mortality in patient with UA. Moreover, although the use of clopidogrel is recommended in some evidences for patients with UA, it is not necessary in this case as SA is associated with very low risk of cardiovascular events. In conclusion, the acute management and the long-term management of UA in SA are generally evidence-based.
1373, Penang, Malaysia.
Date of Birth (Age)
Social History Housewife; Stays with 7 childrens
Non-smoker, Non-alcoholic drinker
Family Medication Historty None
PATIENT HOSPITAL STAY
Presenting complaint in primary care / reason for admission
Admission date : 04/04/2009
Chest pain; giddiness; shortness of breath; palpitation
Discharge Date : - Discharged to: -
RELEVANT MEDICAL HISTORY
RELEVANT DRUG HISTORY
40mg three times daily
75mg once daily
As antiplatelet agent
Type II Diabetes Mellitus
500mg three times daily
5mg twice daily
RELEVANT NON DRUG TREATMENT : None
DRUGS DURING CURRENT ADMISSION
Dose & Frequency
S/C Enoxaparin (100mg/ml)
60mg immediately, follwed by 60mg every 12 hours ïƒ total 6 doses
300mg immediately, followed by 75mg once daily
Unstable Angina / Hypertension
25mg immediately, followed by 50mg twice daily
Unstable Angina / Hypertension
20mg at night
Lipid Lowering Agent
S/C Humulin R
(Regular Human Insulin)
- 100 units/ml
8 units three times daily
500mg three times daily
5mg twice daily
S/L Glyceryl Trinitrate
0.5mg immediately, and 0.5mg when required
80mg twice daily
4mg once daily
Type II Diabetes Mellitus
CLINICAL/ LABORATORY Tests
>0.04ng/L (cardiac injury)
>0.5ng/L (suspected AMI)
M: 1-10 mm/hr
Plasma Total Cholesterol
Desirable < 5.17 mmol/L
Borderline 5.17-6.19 mmol/L
High Risk > 6.19 mmol/L
Desirable < 1.7 mmol/L
Borderline 1.7-5.84 mmol/L
High Risk > 5.84 mmol/L
Desirable < 3.36 mmol/L
Borderline 3.36-4.12 mmol/L
High Risk > 4.12 mmol/L
Desirable > 1.29 mmol/L
High Risk < 1.29 mmol/L
Total Cholesterol/ HDL-Cholesterol
Desirable < 3.8
High Risk > 5.8
PHARMACEUTICAL CARE PLAN
Confirm medication history
Obtain information regarding medication history from both the patient and the prescriber.
Medication history confirmed.
Patient suffered from chest pain on first day of admission
a. Sublingual glyceryl trinitrate 0.5mg should be given as immediate management for relief of chest pain.
b. It can be given up to 3 doses with interval of 5 minutes. If ineffective, intravenous glyceryl trinitrate should be considered.
c. Sublingual glyceryl trinitrate 0.5mg can be given when required as long term management.
[ACC/AHA Practice Guideline; SIGN 93]
Sublingual glyceryl trinitrate 0.5mg was given to the patient on second day of admission.
Increased risk of bleeding due to an overdose of enoxaparin
a. Review the dose of enoxaparin (1mg/kg every 12 hours).
- body weight of patient is 46kg
b. Discuss with prescriber regarding the overdose of enoxaparin.
c. Monitor signs of bleeding as there was an increased risk of bleeding.
a. It is an overdose as 46mg of enoxaparin should be given to the patient instead of 60mg.
b. Discussed with prescriber but no dose change has been made.
c. Patient has no signs of bleeding.
High risk of bleeding due to the concurrent use of enoxaparin and aspirin
(aspirin enhances anticoagulant effects of enoxaparin)
a. Advice patient to be aware of this issue and to seek medical help if there are signs of bleeding e.g. unexplained brushing.
b. Monitor carefully and suggest to have full blood count (FBC) test in case of suspected bleeding.
Patient has no signs of bleeding.
The use of clopidogrel as an additional antiplatelet agent in long-term management of unstable angina is recommended in some practice guideline and its effectiveness is shown in several clinical trials.
Discuss with prescriber regarding the use of dual antiplatelet therapy: aspirin 75mg once daily (for life-long treatment) and clopidogrel 75mg once daily (at least one month) as part of management.
[ACC/AHA Practice Guideline; SIGN 93]
Aspirin 75mg once daily was given to the patient. No clopidogrel was given to patient.
The management of hypertension is inadequate.
(only beta-blocker was given to the patient and the blood pressure was fluctuating throughout the period of hospital admission)
a. Discuss with prescriber regarding the use of ACE inhibitor (perindopril) as it is the first line medication in the management of patient with hypertension, especially those with age less than 55 years old.
b. Make sure the use of beta-blocker together with perindopril is in a long-term basis.
c. Monitor the blood pressure of patient more frequently.
Target blood pressure: <140/80mmHg
d. Review blood pressure profile of the patient after two weeks for further perindopril dosage increment (up to 8mg once daily if tolerated).
[BNF 55, Sec.2.5.5, pg.103; NICE 18, NICE 66]
a. Perindopril 0.5mg once daily was only given on third day of admission.
b. Perindopril was used together with metoprolol.
c. Patient's blood pressure was measured four hourly during admission.
d. Not done.
Further investigation needed to confirm the cause of anaemia
[low Hb, low haematocrit, low MCV ïƒ microcytic anaemia (suspected iron deficiency anaemia)]
a. Perform test on patient's serum iron level, ferritin level and total iron binding capacity.
b. If serum iron and ferritin is lower than normal range while total iron binding capacity is higher than normal range, iron supplement should be given to the patient. (dried ferrous sulphate 200mg three times daily).
c. Review the level of haemoglobin after 3-4 weeks to make sure it reaches reference range. Treatment would then be continued for further 3 months to replenish iron stores.
[Pharmacotherapy handbook 7th edition; BNF 57]
Low level of plasma albumin and urea, which may result from insufficient intake of protein.
[patient's kidney and liver functions are normal, so there is low possibility to be associated with kidney and liver disease]
a. Perform further test on kidney and liver function to make sure that hypoalbuminemia is not associated with any kidney or liver diseases.
b. Check the signs of malnutrition, like weight loss, weakness or dry scaly skin.
c. Assess the dietary habit of patient to make sure that she is on balanced diet.
d. Monitor signs of oedema as hypoalbuminemia is always associated with face oedema, ankle oedema or leg oedema.
e. Advice patient on balanced diet and increases intake of food with high biological value of protein, like fish, peanut and soybean).
[Pharmacotherapy handbook, Medscape]
Management of mild hypokalaemia (may result from inadequate potassium supplementation)
a. Potassium supplement should be given to the patient, such as potassium chloride or potassium bicarbonate.
b. Monitor potassium level by performing regular test to make sure the level of potassium is restored to normal level.
Discontinuation of statin therapy on third day of admission is inappropriate
a. Make sure continuation of long-term statin therapy as it is important for secondary prevention of cardiovascular events in patient with hypertension, unstable angina and diabetes mellitus.
b. Suggest regular lipid profile checking during hospital stay and consider statin dosage increment (up to 80mg daily) if patient's condition is not improved with current dosage.
[ACC/AHA Practice Guideline; SIGN 93; NICE 66]
It is inappropriate to discontinue both insulin therapy and glibenclamide at the same time as the cause of hypoglycaemia is unknown
a. Assess the cause of hypoglycaemia.
b. Insulin therapy should be terminated first, then review the blood glucose profile.
c. If blood glucose is still maintained at a very low level, then only replace glibenclamide by a shorter-acting oral sulphonylurea (gliclazide).
d. Provide intensive monitoring of blood glucose level (every 4 hours) during admission.
Adverse effects of long-term use of statin therapy
(risk of liver impairment and myopathy)
a. Monitor liver function, especially liver enzyme level. If liver enzyme levels are raised 3 times higher than the reference range, statin therapy should be stopped and medical help should be seek promptly.
b. Advice patient to report any unexplained muscle pain, tenderness and weakness. If any of these symptoms exists, discontinue the statin therapy and seek medical help.
a. Liver function of patient was being monitored.
b. Patient was aware of the adverse effects.
Prevention of diabetic complications (diabetic retinopathy, neuropathy, nephropathy, diabetic foot)
a. Suggest fasting blood glucose test, HBA1c to be done.
b. Tight control of fasting blood glucose with target HBA1c < 7%.
c. Keep blood pressure and cholesterol level under control.
d. Advice patient on importance of being compliance for optimal control of blood glucose level.
e. Perform regular screening for complications (at diagnosis and annually thereafter) so that early diagnosis of complications can be achieved and early treatment can be given as well.
f. Advice patient to maintain personal hygiene and foot-care to prevent diabetic foot. Advice patient to consult doctor if there is any blister, cut or swelling being found on foot.
[SIGN 55, CPG 2004 Malaysia]
Patient education on lifestyle modification and importance of compliance
a. Advice patient on the importance of performing regular physical exercise (approximately 30-60 minutes 3-4 times every week).
b. Advice patient on the importance of maintaining balanced and healthy diet (low salt intake, low saturated fat, high fibre, carbohydrate with low glycaemic value, increase protein intake).
c. Explain the importance of being compliance to the treatment.
[SIGN 93, SIGN 55]
Patient understood the need and benefit of lifestyle changes and being compliance in managing her conditions.