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Patient, Mrs. SM, 62 years old retired female with weight of 60kg and height of 152cm. Patient's calculated body mass index was 25.97kg/m² indicating she was overweight. Patient was admitted to the hospital under acute emergency and was complaining on her chest pain which radiated to her left shoulder and associated with sweating. Patient also experienced shortness of breath and complained about nausea and headache.
1.2 Relevant history
Mrs. SM was diagnosed with hypertension eight years ago. She is a non-smoker and she does not drink alcohol as well. There is no relevant information regarding her family history. Patient has been taking hydrochlorothiazide 25mg once daily and metoprolol 100mg twice daily for her hypertension. Aspirin 150mg once daily and simvastatin 40mg at night are given for her secondary ischaemic prevention. Patient is also given sublingual glyceryl trinitrate 500mcg as required for acute relief of ischaemic attack. Patient has no known drug allergy.
1.3 Examination details and diagnosis
The patient's plasma troponin I and creatine kinase were traced on the day of admission. The troponin I level was 2.69ng/ml whereas her creatine kinase was 263 IU/L. On day 2 and 3, patient's creatine kinase has dropped to 176 IU/L ad 92 IU/L respectively. It is important for sample to be taken for diagnosis or prognostic risk stratification after 12 hours of onset of symptoms. Elevated troponin I level and creatine kinase indicated that patient had myocardial infarction. ECG of the patient was monitored throughout the admission, and there was no persistent elevation of ST-segment but T-wave inversion was identified. Thus, diagnosis of acute coronary syndrome with non-ST segment elevation myocardial infarction, underlying hypertension was made. Laboratory results showed that patient's renal profile was normal. Her lipid level was under control and random blood glucose level was within the reference range.
1.4 Clinical progress and management plan
On examination, patient was alert, with her blood pressure was 150/89 mmHg and pulse rate was 69 beats per minute. Patient current chest pain has improved and there is no more shortness of breath after giving aspirin 300mg and GTN 500mcg when she was admitted to hospital. Electrocardiogram for this patient had identified a T wave inversion and patient's lung was clear. Patient's management plan was to perform electrocardiogram again. She was then started with aspirin 150mg once daily, sublingual GTN 500mcg as required, subcutaneous enoxaparin 60mg immediately and then twice daily. She was then continued with her old hypertension medications and simvastatin.
On Day 2, patient's blood pressure remained high with 149/80 mmHg and her pulse rate was 60 beats per minute. Patient claimed that her left sided chest pain was less with no radiating. She has no longer feeling shortness of breath and palpitations. Her management plan was to review her electrocardiogram and continue with her previous medications. She will also be started on amlodipine 10 mg once daily in order to control her elevated blood pressure.
On Day 3, patient generally felt comfortable and alert with no more chest pain and shortness of breath. Her blood pressure decreased to 135/72 mmHg and her pulse rate was 64 bpm. Patient's management plan included to continue with her previous medications and observations.
Patient's blood pressure was 130/77 mmHg and her pulse rate was 60bpm on Day 4. She was also completed her six doses of subcutaneous enoxaparin. Patient will be discharged with all her old medications with amlodipine 10mg once daily added to further control her blood pressure. Patient was arranged for a stress test at outpatient department and she was also reminded to come back for review five weeks later.
1.5 Pharmaceutical Care Issues
On admission, Mrs. SM was enquired about her past medication history. Confirmation was done by asking her family member to bring her current medication on the following day to ensure that correct drug history was listed with exact drugs being prescribed to the patient during admission.
Patient's blood glucose was found elevated high when she was admitted to the hospital with 150/89mmHg on Day one and 149/80 mmHg on Day 2. Her blood pressure need to be controlled and ideally should be <140/80mmHg in order to reduce the risk of second ischaemic attack. Patient was previously prescribed with hydrochlorothiazide and β-blocker for her hypertension. According to the hypertension management guideline, a third drug can be added in to facilitate patient's blood pressure controlling. Patient was then prescribed with a calcium channel blocker, amlodipine 10mg once daily as add on therapy and her blood pressure was managed to be controlled.
There are several clinical risk stratification scoring systems that use to predict death or myocardial infarction in patients with ACS. GRACE is one of them, and it is useful to clinicians to guide the treatment suitable for the patient. According to the GRACE risk stratification tool, Mrs. SM was at low risk of in-hospital death. She should be on aspirin, clopidogrel, ACE inhibitor, β-blocker, statin and low molecular weight heparin1. Patient was already on 300mg of aspirin once daily, 100mg of metoprolol twice daily in conjunction with her hypertension 40mg of simvastatin and 6 doses of enoxaparin. However, there was no clopidogrel and ACE inhibitor being prescribed. Patient should be given 300mg of clopidogrel initially, followed by 75mg once daily up to at least one month, ideally up to 12 months1. Patient should also be prescribed with perindopril, 2mg once daily for a week, then 4mg once daily for another week, thereafter increase to 8mg once daily if she is able to tolerate2.
Patient was prescribed with aspirin and low molecular weight heparin for the first few days in order to reduce the risk of myocardial infarction and death. However the concurrent use of these two drugs will increase the risk of gastrointestinal bleeding and ulceration. Hence, patient needs to be monitored with any signs of unexpected bleeding, bruising and gastrointestinal discomfort.
On Day 4, patient will be discharged due to her improvement. It is important to ensure that all medications that need to be carried on are prescribed as discharge medications with appropriate doses. Based on patient's condition, she should be prescribed with aspirin, clopidogrel, simvastatin, metoprolol, perindopril, glyceryl trinitrate, hydrochlorothiazide and amlodipine as her discharge medications. However, patient was not prescribed with clopidogrel and perindopril.
From the patient calculated BMI, it was indicated that patient is overweight and she needs to be counseled on the risk of overweight and encouraged to lose weight. Patient should also be encouraged to maintain healthy lifestyles by taking regular exercise, increase fruits and vegetables consumption with at least 5 portions per day as well as reduce saturated fat intake. Compliance is a crucial issue and patient need to be informed about the importance of compliance and counseled appropriately on the doses, indications and possible side effects of her prescribed mediations prior to discharge.
Lastly, patient with myocardial infarction need to be reviewed 5 weeks after the ischaemic attack. An appointment should be arranged and the patient should be reminded to attend the follow up review.
Disease overview and pharmacological basis of drug therapy
2.1 Acute coronary syndrome-NSTEMI
Acute coronary syndrome (ACS) can be classified into two main groups namely ST-elevation myocardial infarction (STEMI) and non ST-elevation ACS (NSTEACS) which includes non ST-elevation myocardial infarction (NSTEMI) and unstable angina (UA)1. ACS is the major issue that contributes to mortality and morbidity rates in Western countries3. In Britain, the annual incidence rate of ACS is estimated to be 1.1 cases per 1000 males and 0.5 cases per 1000 females at aged 31-70 years3. NSTEMI has also accounted for 2.5 millions of hospital admission worldwide3. ACS happens as a result from years of atherosclerotic plaque build-up which over the time thicken and rupture, exposing a thrombogenic surface where platelets can aggregate and forming thrombus4. This cause the narrowing or completely blocking of the coronary arteries and lessening blood flow to the heart muscle, deprive the oxygen supply to the heart muscle4. Myocardial necrosis occurred due to oxygen insufficiency and the damaged cardiac tissues will synthesis various cardiac biomarkers which are used to diagnose myocardial infarction. Besides the biomarkers such as Troponin T, electrocardiogram (ECG) as well as symptoms of ACS including chest pain typically radiates to the left arm, shortness of breath, nausea, palpitation and sweating can be used to diagnose ACS.
When managing NSTEMI patients, the pharmacological therapy includes antithrombotic drugs like aspirin, clopidogrel heparin, GPIIb/IIIa inhibitors and anti-ischaemic drugs such as β-blockers and nitrates. Other drugs like statin and ACE inhibitors also add in to facilitate the therapy. Aspirin, a cyclooxygenase inhibitor, works as antiplatelet by decrease the platelet aggregation and thus inhibit formation of thrombus in the artery5. Aspirin has a short half life of 5-15 minutes and it acts quickly with effect that lasts for 10 days of a platelet lifetime5. Clopidogrel is a thienopyridines derivative which is a potent and non-competitive adenosine diphosphate (ADP) receptor antagonist6. When binds to the platelet membrane ADP receptor, clopidogrel can inhibit the ADP-induced platelet aggregation6. It also able to affect glycoprotein IIb/IIIa receptors thus reduces platelet activation6. NSTEMI patients often treated with combination therapy of aspirin and clopidogrel since this offers more benefits that uses the drug alone7. Besides aspirin and clopidogrel, heparin also acts as antithrombotic drug in managing NSTEMI patients. Heparin can be classified into unfractionated and low molecular weight heparin. Heparin acts by interfering the coagulation cascade by activates antithrombin III to inhibit clot formation4.
Long term β-blockers therapy is also used in NSTEMI patients unless contraindicated since it reduces mortality and sudden death1. β-blockers has cardio-protective property and can reduce heart rate and hence the cardiac workload. It should not be used in patients who suffer from asthma, bradycardia and hypotension1. Nitrate is also used in NSTEMI patients for acute relief of cardiac pain by causing vascular smooth muscle relaxation. It dilates the artery to increase the blood flow and oxygen supply to the heart. Patients with NSTEMI should be started with long term statin therapy. Statin is a lipid lowering drug, acts by reducing the synthesis of cholesterol that promotes atherosclerosis. Long term ACE inhibitor therapy should be commenced on patients with ACS1. It is a potent vasoconstrictor and acts by reducing workload of heart through arterial pressure reduction4. ACE inhibitor has proved to be beneficial in reducing morbidity as well as mortality in NSTEMI patients1.
Hypertension is usually asymptomatic and can be documented as a risk factor in ACS patients. In UK, there are approximately 1 in 4 middle-aged adults, and almost half of people who over 65 years old, are suffer from hypertension8. There are two categories of hypertension, namely essential and secondary hypertension. The cause of essential hypertension is normally unknown whereas secondary hypertension is due to other illness conditions which lead to hypertension. Those with blood pressure (BP) <140/90mmHg are considered hypertensive and should be treated before any complications. The drugs used to treat hypertension including thiazide, β-blocker, calcium antagonist, ACE inhibitor, angiotensin II antagonist and α-antagonist.
Thiazide acts on distal convoluted tubule and inhibit sodium-chloride transporter, decrease the sodium reabsorption, hence increase water loss to urine4. Thiazide will then decrease the preload and then blood pressure. β-blocker can reduce the cardiac output, alter baroreceptor reflex sensitivity as well as block the peripheral adrenoceptors, causing it to be effective in reducing blood pressure8. Calcium antagonist reduce BP by prevent Ca2+ enter the artery vasculture cells, result in vasodilation, and reduce the peripheral vascular resistance8. ACE inhibitor causes reduction in peripheral resistance thus decrease the BP whereas angiotensin II antagonist reduce BP through suppression of vasopressin and aldosterone secretions8. α-antagonist are also used to reduce BP through peripheral resistance and preload reduction8.
When managing elderly patient with hypertension, the first option is using thiazide diuretic, follow by β-blocker as alternative or supplementary therapy if thiazide alone is insufficient9. Long acting dihydropyridine calcium antagonists can then be added if another supplementary therapy is needed9. It is particularly beneficial in patients with isolated systolic hypertension9. The BP target goal for elder patient with cardiovascular events should be <130/80mmHg.
Evidence for treatment of the conditions
3.1 NSTEMI management
Evidence of using aspirin in management of NSTEMI
First of all, patient with NSTEMI should be on long term aspirin therapy (75-150mg) according to the SIGN guideline. Aspirin is found to be protective in most type of patients with increase risk of occlusive vascular events. This is supported by a study where aspirin therapy halves the rate of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke by absolute risk reduction (RR) of 5.3%, relative risk reduction of 46% in patient with unstable angina compared to placebo group1, 10. Aspirin also reduce the risk of vascular events of the acute myocardial infarction patient group by one third with absolute RR of 3.8% and relative RR of 30% compared to placebo group1, 10. The doses of aspirin most widely studied were 75-150mg, with doses lower than 75mg provided less certain results10.
From the aspect of gender, low dose aspirin therapy was found to be beneficial in both men and women in reducing cardiovascular events. A meta-analysis which involved total patients of 95456, where women comprised of 53% showed that aspirin therapy resulted in a significant reduction of 12% (odd ratio (OR) =0.83) in cardiovascular events with p<0.0511. Similarly, aspirin therapy caused significant reduction of 14% (OR=0.86) in cardiovascular events and 32% (OR=0.68) reduction in myocardial infarction among the male subjects11. However, aspirin therapy also significantly increases the incidence of bleeding in both males and females. Therefore, the decision that patient on aspirin therapy is appropriate but need to be monitored on any signs of unexpected bleeding or bruising.
Evidence of using combination therapy of low dose aspirin and clopidogrel
In a published trial, patients who presented within 24 hours after the onset of NSTEMI symptoms were randomised to receive either clopidogrel with 300mg of loading dose immediately, follow by 75mg of maintenance dose or placebo7. Both groups of subjects took aspirin in addition to either clopidogrel or placebo for duration of 3-12 months7. The results evaluated that combined therapy of aspirin and clopidogrel was more effective compared to aspirin therapy alone7. Among the subjects involved in the trial, 9.3% of the clopidogrel group and 11.4% of placebo group died due to cardiovascular events or experienced non-fatal myocardial infarction or stroke7. This has corresponded to a significant reduction in combination therapy of clopidogrel and aspirin with relative RR of 20%7. Besides, the composite of the death from cardiovascular events, non-fatal MI, stroke along with refractory ischaemia also happened in 16.5% of clopidogrel group and 19% of placebo group7. This showed a significant reduction of 14% in relative risk7. Therefore, the patient in this case should be on clopidogrel therapy in addition to low dose aspirin therapy.
Evidence of using low molecular weight heparin
From a trial which recruited 3171 random patients with unstable angina or NSTEMI, low molecular weight heparin has showed benefits in the acute phase treatment of these patients. Both groups of patient receive aspirin therapy daily with one of the groups of this double-blinded trial receive subcutaneous enoxaparin (1mg/kg) two times per day whereas the other group receive continuous intravenous infusion of unfractionated heparin12. The duration of both treatments lasted for 2-8 days12. The results showed a significant lower incidence of risk of death, myocardial infarction or recurrent angina in enoxaparin group (16.6%) than unfractionated heparin group (19.8%) 12. A one year follow up trial has been carried out in order to investigate the benefits of enoxaparin were sustained after early phase. The results showed that the benefits of enoxaparin were significantly sustained12. The incidence of death, MI or angina recurrent was also significantly lower than unfractionated heparin group with 32% versus 35.7%12. In addition, when comparing the need for diagnostic catheterisation as well as coronary revascularisation, enoxaparin group has lower incidence with 55.8% and 35.9% compared with 59.4% and 41.2% in unfractionated heparin group correspondingly12. Hence, Mrs. SM was treated with enoxaparin 60mg twice daily for 3 days is therefore appropriate.
Evidence of commencing statin therapy
From a five-year study which involved 4444 of patients with total cholesterol levels of 5.5 to 8.0 mmol/L with initial treatment of 20mg of simvastatin, then titrated to either 10mg or 40mg, it was showed that simvastatin treatment had reduced the major coronary event by 34% and the cardiac death rate by 42%13. This study is further supported by a meta-analysis of randomised controlled trials which recruited 30817 of patients with mean duration of statin treatment of 5.4 years14. The results showed reduction of 31% of the major coronary events with and the risk reduction is more or less similar among men and women with 31% and 29% respectively14. Since statin therapy is able to reduce the risks of coronary events and cardiac death, 40mg of simvastatin therapy is suitable for Mrs. SM.
Evidence of using β-blocker in NSTEMI patient
From SIGN guideline, the first line anti-ischaemic drug for patient with non-ST segment elevation acute coronary syndrome is β-blocker1. In a randomised study, the benefits of metoprolol in patients survived from acute myocardial infarction were evaluated15. 154 patients were recruited in metoprolol treatment group where they will be given 100mg twice daily15. On the other hand, a matching number of patients were also recruited into the placebo group. The results showed a significant reduction of cardiac death with 12.5% in the metoprolol group and 32.1% in the placebo group15. The incidence of non-fatal re-infarction was also significantly lower in treatment group (11.7%) compared with placebo group (21.1%) 15. Moreover, the sudden date rates also significantly lowered in treatment group than placebo group with 5.8% and 14.7% respectively15.
A systemic review which recruited 54234 of patients showed that β-blocker is beneficial as secondary prevention in myocardial infarction16. Long term use of this drug has shown to further reduce the incidence of mortality. There is significantly 4% reduction of death incidence in short term use whereas long term use of β-blocker comprised of 23% reduction in mortality16. From the above studies, it is rational for Mrs. SM to continue with her metoprolol 100mg twice daily as secondary preventative therapy as well as to treat her hypertension.
Evidence of using ACE inhibitor in treating NSTEMI patients
Patient with NSTEMI should be given ACE inhibitor therapy as long term prevention since there are various trials demonstrated significant reductions in proportional mortality rate as well as the incidence of non-fatal cardiac events17. Apart from that, a trial which involved large population of patients (n=12261) with ischaemic heart disease also supported the use of ACE inhibitors18 has secondary benefits. From the study, randomised patients were treated with 8mg of perindopril versus placebo for duration of 4.2 years18. The results indicated that patients in perindopril group significantly experienced fewer cardiovascular events and myocardial infarction by 20% as compared with placebo group18. A trend of further significant reduction of 14% and 22% in cardiovascular mortality and non-fatal myocardial infarction correspondingly was demonstrated from the study18. Hence, it is appropriate to prescribe an ACE inhibitor, perindopril 2mg once daily for a week, then 4mg once daily for another week, thereafter increase to 8mg once daily if patient is able to tolerate2.
3.2 Hypertension Management in Elderly
Evidence of using thiazide as first line treatment
A meta-analysis had been carried out to review the safety as well as efficacy of several antihypertensive drugs as first-line agents in terms of stroke, congestive cardiac failure and coronary disease19. The long-term use of diuretics and beta blockers had been investigated in 18 randomised placebo-controlled trials19. The results showed that diuretic therapy was effective in stroke prevention with relative RR of 0.49 and 0.17 for congestive cardiac failure19. Similar results were obtained for the trials of beta blockers where relative RR for stroke is 0.71 whereas congestive cardiac failure has relative RR value of 0.5819. Despite the similar results obtained from previous trial, another study had demonstrated thiazides are more preferable than other drug classes in terms of efficacy, quality of life and also cost20. Moreover, a study that recruited 16164 of patients with age ≥60 years old has showed that the blood pressure of two third of subjects in diuretic group managed to be controlled using diuretic monotherapy21. On the other hand, there were only one third of subjects that assigned with β-blocker managed to control their blood pressure21. Diuretics monotherapy also showed superiority over β-blocker monotherapy in reducing the incidence of cardiovascular events, stroke, coronary artery disease, cardiac death as well as all-cause mortality21.
Evidence of using β-blockers as supplementary therapy after thiazide
The effect of β-blockers added in as supplementary therapy in blood pressure reduction was reviewed in a trial where 3744 of patients were recruited, showed 6/4mmHg reduction at 1 time of manufacturer recommended dose whereas 8/6mmHg of reduction was shown in patients took 2 times of the recommended starting dose22. Overall, there is an additional reduction in blood pressure when a β-blocker is added in. A further 30% reduction was shown if the dose was doubled than the starting dose recommended22.
Evidence of using Amlodipine in managing hypertension
A double-blind, placebo randomised controlled study had been carried out on a group of mild to moderate hypertensive patients. The dose of amlodipine initially administrated was 2.5mg and tititrated up to 10mg at 2 weeks intervals for 8 weeks23. Amlodipine had shown a significant reduction of 16/12 mmHg of blood pressure in supine position and 14/4 mmHg when standing23. Patients' blood pressure was then found to return to baseline once the therapy was withdrawn and the effects of amlodipine was washed out using placebo23.
Amlodipine was also shown to be an effective antihypertensive agent and is well tolerated as either monotherapy or in combination therapy with other antihypertensive agents24. From the 18 clinical studies which recruited a total of 1896 patients, the amlodipine group showed significant reduction in blood pressure, indicated amlodipine played a role in controlling blood pressure24. Moreover, 5-10mg of amlodipine was also well-tolerated with other agents like β-blocker, thiazides or ACE inhibitor24.
As a conclusion, although the pharmacology managements of Mrs. SM is generally appropriate and evidence based, Mrs. SM should be prescribed with clopidogrel as well as ACE inhibitor in order to maximise the patient's benefits. It has been proved that loading dose of 300mg of clopidogrel, follow by a maintenance dose of 75mg in combonation with low dose aspirin has significant benefits in re-ischaemic prevention. ACE inhibitor also showed significant effect in secondary prevention of ischaemics, especially perindopril which accounts 20% reduction in cardiovascular events and re-ischaemic than placebo groups18. Therefore, Mrs. SM should be prescribed with 2mg of perindopril once daily for a week due to her age2. The dose can be increased up to 4mg for another week and increased up to 8mg thereafter if patient is able to tolerate with the dose2. From the SIGN guideline, GPIIIb/IIa has proven been beneficial, reduce mortality rate and cardiac events in high risk patient1. The risk stratification of Mrs. SM showed that she is of low risk on in-hospital death, hence GPIIIb/IIa is not necessary for her. In conjunction with patient's hypertension management, 100mg of metoprolol twice daily is rational since metoprolol not only can reduce patient's blood pressure, it also acts as secondary prevention of cardiac events.