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Acute coronary syndromes encompassed unstable angina to myocardial infarction and sudden death. In the United Kingdom, around 2 million people over 35 are living with angina during 2009. From these, around 1.15 million are men while around 860,000 are women. (BHF) Most hospital admissions are due to acute coronary syndromes. There are around 114,000 patients that are admitted to acute hospitals in the United Kingdom due to acute coronary syndromes patients each year. Most patients are sent to general hospitals that have no facilities for revascularisation. The primary goal of care is medical stabilization. Within 6 months of the first episode of acute coronary syndrome, almost one third of the patients will either die or progress to a further episode of acute coronary syndromes such as myocardial infarction or unstable angina that resulted in hospital readmission. (bakhai)
Angina pectoris can be described as a symptom of myocardial ischaemia that is reversible. It is commonly experienced as intense chest pain due exertion that can be relieved by rest. The symptoms were caused by insufficient supply of oxygen to cope with oxygen demand in the ischaemic area of myocardium. This is usually due to a fixed atheromatous narrowing of coronary artery that causes the decrease ability of coronary blood flow to increase and meet the metabolic demands of the heart. (Waller Renwick) Unstable angina is also associated with sweating, breathlessness, palpitations or nausea. (oxford)
All heart diseases under acute coronary syndrome share a common pathophysiological origin in coronary artery artheromatous plaque that is unstable. Atheroma occurs extensively in the coronary artery of people who smoke, have hypertension or hypercholesterolaemia at a younger age. Atheromatous plaques can be relatively unstable if they have lipid-rich cores that are infiltrated with inflammatory cell and covered by a thin fibrous cap. However, some are more stable as the cores are more fibrotic and covered by a thick, fibrous cap. The plaques' properties determined the resulting acute coronary syndrome. The unstable plaques can be disrupted by sudden stresses on the fibrous cap due to vasospasm and local disturbance of blood flow. As a result of the fissure or ulcer development on the plaque surface, platelet aggregation occurred. This caused thrombus formation and local vasospasm. Microemboli that are formed from platelet and thrombin can break off resulting in blood clots at small distal vessels. (Waller Renwick)
Angina will occur on minimal exertion if occlusion of the vessel is incomplete. However, angina will occur at rest if the occlusion of the vessel is almost complete. In unstable angina, the occlusion last for about 20 minutes as thrombus is spontaneously lysed and local vasospasm is reduced. Then ischaemic tissue will received blood supply without any permanent damage. This is the reason the duration of unstable angina symptom of chest pain last for more than 20 minutes. Increased occlusion time leads to myocardial infarction. (Waller Renwick)
According to NICE guidelines, the diagnosis of acute coronary syndrome such as unstable angina and myocardial infarction depends on clinical presentation of patient regarding history of coronary artery disease, electrocardiographic changes and biochemical cardiac markers such as troponin I or T, creatinine kinase MB and other cardiac enzymes levels. Troponin I and T are sensitive cardiac markers that may increase in concentration during myocardial injury and damage. (Nice) Unstable angina can therefore be diagnosed when troponin T concentration is lowered than a certain level as shown in Table 1.
Table 1 NICE guideline troponin T concentration definition and prognosis of acute coronary syndrome.
12 hr serum troponin T concentration (µg/l)
> 0.01 and < 1.0
ACS with unstable angina
ACS with myocyte necrosis
ACS with clinical myocardial infarction
ESC / ACC definition
SIGN guideline recommended an initial management plan of unstable angina during the first 12 hours. Patients that are suspected of suffering from acute coronary syndrome should be on continuous cardiac rhythm monitoring. Oxygen therapy should be given to patients that are hypoxia, have pulmonary oedema or continuing myocardial ischaemia. Upon admission, 300 mg of aspirin should be given to patients with acute coronary syndrome immediately. 300 mg of clopidogrel can be added to patient medication with low molecular weight heparin immediately in the events that there are changes in ischaemic electrocardiographic and cardiac markers elevation. Those that are deemed high risk with non-ST elevation acute coronary syndrome especially those undergoing percutaneous coronary intervention should be administered with an intravenous glycoprotein IIb/IIIa receptor antagonist. Intravenous or oral beta blockers are recommended immediately if the patient does not have bradycardia or hypotension. (sign) nitrates morphine (uaa aha)
After the initial management of unstable angina, patient should be maintained on long term therapy of 75-150 mg aspirin per day. In addition, if the patient was started on clopidogrel, long term therapy of 75 mg should be continued for 3 months for clinical benefits. Prior to hospital discharge, patients that have suffered from unstable angina should be commenced on long term statin, beta blocker and ACE inhibitor therapy in patients with unstable angina to prevent future recurrence. Calcium channel blocker is an alternative if beta blocker is not tolerated by patient.(?) ACE inhibitor can be replaced by angiotensin receptor blockers if ACE inhibitor cannot be tolerated by patient. Nitrates can be used in acute coronary syndromes to relieve cardiac pain. The mechanism of action of drugs used in the case is shown in table 2 below.
Table 2: Mechanism of action of unstable angina drugs used in the case. (Waller renwick)
Aspirin selectively inhibit platelet cyclooxygenase type 1 irreversibly which reduces platelet thromboxane A2 production. This reduces platelet production which reduces blood coagulation.
Enoxaparin bind and increase inhibitory antithrombin III effect on factor Xa which reduce thrombin formation. This inhibits platelet aggregation by interacting with platelet activation.
Beta blockers act as competitive antagonists of catecholamines at beta-adrenoceptor. Atenolol is a selective cardiac β1 blocker. It inhibits sympathetic stimulation and cause reduction in heart rate, cardiac output and blood pressure.
Glyceryl trinitrate and isosorbide dinitrate are nitrate vasodilators that work by mimicking endogenous nitric oxide. Nitrate degraded to become nitric oxide and nitric oxide combined with thiol groups to form nitrosothiols. Nitric oxides together with nitrosothiols activate guanylate cyclase and generate cyclic guanosine monophosphate which reduces intracellular Ca2+ for vascular smooth muscle contraction mechanism and this causes relaxation. Vasodilation is produced in venous capacitance vessels, arterial resistance vessels and coronary arteries but mainly on venous capacitance vessels by decreasing venous return and preload on heart. This reduces myocardial oxygen demand.
Morphine acts as an agonist and binds mainly at µ-opioid receptors which produce analgesic and anxiolytic effects.
Lovastatin competitively inhibit 3-hydroxy-3-methyl-glutaryl-CoA reductase that is essential in cholesterol production by liver. This reduces cholesterol level.
Perindopril competitively inhibit angiotensin converting enzyme (ACE) which block the conversion of angiotensin I to angiotensin II. This consequently decreases the release of aldosterone. Angiotensin II concentration reduction bring about mainly arterial and venous dilation. This decreases cardiac load and arterial pressure.
Evidence for treatment of the condition(s) (1500-1800 words)
Meta-analyses of randomised trials that have been previously conducted demonstrated protective effect of antiplatelet therapy in serious vascular events, venous thromboembolism and arterial occlusion among high risk patients with occlusive vascular events such as those with myocardial infarction, stroke or unstable angina. Antiplatelet therapy proportionally reduced a quarter of serious vascular events such as myocardial infarction and stroke regardless of sex, age, blood pressure or diabetes history. Antithrombotic Trialists' Collaboration of meta-analysis showed reduction of 22% in vascular death, stroke or myocardial infarction from 143,000 over patients in 195 trials that include a wide range of patients including those with unstable angina. Aspirin was shown to halve the rate of vascular events in patients with unstable angina compared to placebo with absolute risk reduction of 5.3% and relative risk reduction of 46%. In addition to benefits of antiplatelet therapy for short term treatment of patient with suspected unstable angina, the meta-analyses support the benefit of long term aspirin therapy as secondary prevention in patients with coronary heart disease with an absolute risk reduction of 2.7% and relative risk reduction of 37%. (Sign 93) 75-150 mg of aspirin daily was considered to be an effective long term antiplatelet regimen to prevent serious vascular events as cyclo-oxygenase is almost fully inhibited within the first few days, producing decreased platelet aggregation. Higher doses of 500-1,500 mg aspirin does not increase beneficial effect and can increase the risk of bleeding in stomach. In emergency situation where immediate administration of aspirin is required such as in unstable angina, a loading dose of 150-300 mg should be administered to inhibit platelet aggregation. There had been comparisons regarding effects of different doses of aspirin ranging from less than 75 mg to 1500 mg daily which showed almost similar reductions in vascular events. So, 75 mg to 325 mg dose of aspirin is sufficient to produce beneficial effects. However dose of less than 75 mg demonstrated decreased benefit of aspirin. (Antithrombotic trialists' collaboration)
Clopidrogel can be used as an alternative treatment for patients contraindicated to aspirin.
Low molecular weight heparin
A Cochrane review that takes seven randomised controlled trials with total of 11,092 patients demonstrated that low molecular weight heparin managed to significantly prevent myocardial infarction and coronary revascularisation procedure compared to unfractionated heparin. Low molecular weight heparin that were described in the review were as followed dalteparin, enoxaparin and nadroparin. Only enoxaparin displayed significant result against unfractionated heparin. Overall, there were no reductions of mortality or increased incidence of major haemorrhage between low molecular weight heparin and unfractionated heparin. In patients that were given low molecular weight heparin, it was observed that there were reductions of thrombocytopenia episodes. From Cochrane review results, low molecular weight heparin need to be given to 125 patients to prevent 1 additional myocardial infarction episode and the same goes for 50 patients to prevent 1 revascularization procedure. Compared to unfractionated heparin, low molecular weight heparin significantly prevents overall death, myocardial infarction, recurrent angina and revascularisations in the first 48 hours after treatment and subsequently 3-4 days after treatment. (Cochrane review, magee, sevcik)
The TIMI (thrombolysis in myocardial infarction) 11B trial showed that enoxaparin is better than unfractionated heparin in decreasing death incidences and serious cardiovascular events among patients that have unstable angina. Moreover, as stated earlier, enoxaparin did not cause any significant increase in major haemorrhage. Low molecular weight heparin has no further demonstration of benefits in continued treatment beyond patient's stay in hospital or further than 8 days duration but major haemorrhage may occur more frequently. (Antman EM et al 1999)
An overview of five randomized trials of 4700 patients have shown that beta blockers given initially in intravenous form and subsequently by oral form for a week can produce a reduction of 13% in cardiac ischaemic episodes. Another trial that concerns with usage of beta blockers in unstable angina showed favourable reduction in myocardial infarction while another showed no significant difference. It is postulated that a better, randomized study compromising a larger number of patients with unstable angina are needed to better understand the effects of beta blocker in prevention of myocardial infarction. (Yusuf et al 1988) Another trial compromising 2,894 patients showed association between beta blocker and significant reduction of mortality regardless if patients were undergoing percutaneous coronary intervention or for unstable angina. (ellis, tcheng)
According to sign 93, patients with unstable angina should be maintained on long term beta blocker therapy. (sign 93)
Although oral nitrate therapy did not produce a significant decrease in mortality, oral nitrate seemed to be safe to be taken for 1 month in 2,129 patients allocated with mononitrate. The study did showed that patients allocated with mononitrate encountered fewer deaths on the first 2 days compared to placebo which showed that nitrates can be safely used in early acute myocardial infarction. (isis-4) In another 6-week trial with 19,394 randomised patients, initial intravenous nitroglycerin and transdermal glyceryl trinitrate did not show any significant reductions in overall mortality and severe ventricular dysfunction. (gissi-3) However in another small trial with 162 randomized patients showed significant benefits in chest-related pain attack. Overall, myocardial ischaemia was said to be reduced by intravenous nitroglycerin in the trial among patients with unstable angina. (Karlberg KE, 1998)
In SIGN 93 and ACC/AHA 2007 guidelines, nitrates were recommended in acute coronary syndromes and unstable angina to relieve cardiac pain and treat ischaemic symptoms. (Sign 93) (ACC/AHA 2007)
Patients that present chest pain associated with non-ST-segment elevation acute coronary syndromes were usually treated with intravenous morphine upon admission. However, a study by CRUSADE Initiative has shown that morphine increased mortality rate. Among 57,039 patients either on morphine or intravenous nitroglycerin were analysed and observation shown that patients on morphine has a 6.8% mortality rate compared to 3.8% for patients on nitroglycerin. It was also found that 48% of patients on morphine were at higher risk of dying and 34% will have increased risk of suffering from another myocardial infarction. Furthermore, the higher mortality risk remained after patients' clinical risk starting point was adjusted. The trial recommends that a more suitable, randomized trial that investigate the safety of morphine to be conducted for further information. (meine roe) Currently morphine were not used as first line for chest pain and were only used if ischaemic chest discomfort were uncontrolled by nitroglycerin. (ACC/AHA 2007)
The statin therapy such as simvastatin 40 mg daily or lovastatin 20-40mg daily are established to have beneficial preventative effects on major coronary syndromes. (mrc/bhf) (Downs Clearfield)
In MRC/BHF heart protection study, the effect of simvastatin was investigated against placebo among 20,536 patients with coronary disease and others. It was shown that statin significantly reduced mortality rate by 18% and major coronary events among patients in the study. It was also shown that simvastatin increased benefits when administered together with other major coronary prevention medication. Simvastatin was shown to have no other significant adverse effects.(mrc/bhf) Another study compromising of 6605 people with average total cholesterol was conducted to investigate lovastatin effect in preventing first acute major coronary event. The result of the study showed that after 5.2 years of follow-up, lovastatin managed to reduce the attack of first major cardiovascular events such as unstable angina. It was also stated that statin therapy does not have any other significant adverse effects like simvastatin. (Downs Clearfield) Therefore, statin therapy can be used for long term therapy and some benefits were shown after 4 months of starting statin therapy within one to five days admission of acute coronary syndrome.
(de Lemos JA et al 2004) (Schwartz GG et al 2001) Besides that, a meta-analysis with 17,617 patients that suffered from cardiovascular disease demonstrated that statins reduced risk of major coronary events significantly regardless of gender and age. (larosa) In another trial with 6595 men on pravastatin or placebo, pravastatin was shown to decrease 20% of cholesterol level in plasma and 26% of low density lipoprotein cholesterol level. At the end of the trial, pravastatin was concluded to significantly cause reduction of mortality incidence and major coronary events. (sheperd, cobbe)
ACE inhibitors can cause effective reduction of mortality and morbidity rate among patients with heart failure, hypertension and coronary events. In the EUROPA study, effects of perindopril were investigated against placebo among 12,218 patients. After an average follow up of 4.2 years, the analysis showed significant improvement in prevention of cardiovascular death, myocardial infarction or cardiac arrest by 20% with perindopril. In the period of 4 years, around 50 patients need to be given perindopril for one major cardiovascular event prevention. 8 mg perindopril daily was also shown in the study to be well-tolerated and adverse effects were rare. (Fox KM 2003) Another study called Heart Outcomes Prevention Evaluation (HOPE) includes 9297 patients that have increased risk of cardiovascular factor without low ejection fraction or heart failure were randomised to received either ramipril or placebo. The result showed that ramipril significantly reduced the possibility of mortality, stroke, myocardial infarction, revascularization procedures by at leasts 3%. In the study also states that ramipril was able to produce the same benefits as other secondary preventative treatments such as beta blockers, aspirin and lipid lowering agents for four years of treatment. (yusuf hope ramipril)