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Mr ABC, a 67-year-old male with a BMI of 26.5kg/m2 Height: 1.6m; Weight: 69kg was presented to the emergency department with severe giddiness, headache and sudden onset chest pain at rest. The pain was heavy in nature and resolved after half an hour. He was found to be sweaty and had palpitation. However, he did not experienced shortness of breath, orthopnea and leg oedema was not observed. He had had hypertension which was diagnosed two years ago and last year he was diagnosed with stable angina. His past medical history included:
The patient's social history was that he stays with his wife and children. He claimed to smoke occasionally and he did not drink. The patient has no known drug allergies. It was found that he did not go for follow-up in hospital. He had run out of medication and had not been taking his medication for the past 3 days.
On examination, it was found that his BP was at casualty of 202/125mmHg. Immediately he was started with IV GTN infusion 25mcg/min . He was afebrile (37Â°C), his pulse rate was 86bpm and his respiration rate was 12 beats/min. His cardiovascular, respiratory, abdomen and central nervous system examination results appeared to be normal. His full blood count, coagulation profile, liver function tests were normal. However, his CrCl was found to be 68ml/min which indicated mild renal impairment. There was elevation in his cardiac enzyme as shown in table 1. No abnormalities ware seen in his ECG. The diagnosis of the patient was hypertensive emergency with acute coronary syndrome(UA/NSTEMI).
The management plan for the patient was to keep-in-view to increase IV GTN, started the patient on subcutaneous enoxaparin 60mg twice daily and to continue with the old medication. On day-2, the patient experienced mild headache and no chest pain. However, his blood pressure is still very high with BP measurement of 178/96mmHg. IV GTN infusion was increased to 75mcg/min. His cardiac enzyme test showed a slight elevation in lactase dehydrogenase (LDH) level.
On day-3, the patients experienced minimal headache, he has chest pain on and off. His measured BP was 160/100mmHg which was still quite high. Felodipine once daily was commenced. On day-4, the patient's overall conditions improve, he experienced no chest discomfort, his measured BP was 144/92mmHg. IV GTN infusion was decreased to 25mch/min and slowly weaned off. On day-5, the patient's condition was well and his measured BP was 143/85mmHg and he was to keep-in-view for discharged. Subcutaneous enoxaparin was stopped. Finally, the patient was discharged on day-6 with the following discharge medication:
Worldwide, hypertension affects approximately 1 billion people  . Cardiovascular disease(CVD) is the leading cause of death in Scotland, accounting for more than 18,000 deaths per year  . Hypertension and sub-optimal control of blood pressure (BP) are risk factors that attribute to increase in CVD. Around 1% of hypertensive patients develop hypertensive crisis at some point in their lives  . Hypertensive crisis is characterized as the sudden severe elevation of blood pressure with a systolic BP of more than 179mmHg or a diastolic BP or greater than 109mmHg1,3.
Hypertensive crisis can be further classified into either hypertensive emergency or urgency. Hypertensive emergency is a more serious medical emergency as it is associated with acute end organ damage which often requires immediate intravenous(IV) therapy whereas in hypertensive urgency, no such events are observed and treatment is usually more subtle, requiring the use of additional antihypertensive agents to bring down BP, rarely hospitalization is required  ,  ,  . In both situations, the reduction of BP is needed to prevent impending or further end organ damage. Abrupt reduction of BP in treating hypertensive emergency patients is not advisable as there is a high risk of ischemic or infarction events in target organ due to hypoperfusion of vascular beds  .
The mortality and morbidity of hypertensive emergency depends on the degree of end organ damage and the subsequent BP control. With the appropriate management, the 10-year survival rate of patients with hypertensive crisis approaches 70%  .
Dissecting aortic aneurysm
Acute Left ventricular failure with pulmonary oedema
Acute myocardial ischemia
Acute renal failure
Symptomatic microangiopathic haemolytic anaemia
Table 1: Some of the common end organ dysfunction associated with hypertensive emergency3.
End organ dysfunction such as that shown in Table 1 can be signs of manifestation of hypertensive emergency. However, the sign and symptoms experienced by the patients varied individually depending on the site of organ damage. Patients with hypertensive encephalopathy might develop headache, altered level of consciousness whereas in other patients, hypertensive emergency may manifests as cardiovascular disease such as angina, acute myocardial infarction or acute left ventricular dysfunction3,  .
Pathophysiology & causes
The pathophysiology of hypertensive emergency is not completely understood. However, an abrupt rise in vascular resistance due to release of vascular vasoconstrictor substances or dysfunctions in the body's autoregulatory system are thought to be the triggering event for acute rise in BP. Following the increased in pressure in vessels, endothelial damage occurs in which platelet aggregation and clotting cascade ensues which causes further vascular injury and tissue ischemia. This situation is worsen by situation such as stiffness of blood vessels due to chronic hypertension, or the presence of atherosclerotic plaque. All these reduce the coronary arteries perfusion and increase myocardial oxygen consumption  ,  ,. In the event of hypertensive emergency, the left ventricle fails to compensate for the increased in vascular resistance which might then results in ventricular failure, pulmonary oedema or myocardial ischemia7,  . Myocardial ischemia is one of the most common target organ damage brought about by severe BP elevation4. The most common causes of hypertensive emergency are due to inappropriate control of BP or abrupt discontinuation of antihypertensive medication7.
Patient's history, physical and laboratory assessments are important parameters for determining any end-organ involvement due to complications of severely high BP. Physical examination such as the use of fundoscopic, neurological and cardiovascular examination should be undertaken to assess target organ dysfunction. Laboratory tests that are commonly employed are serum creatinine, urinalysis, electrolyte balance, full blood count, chest X-ray and electrocardiogram (ECG)7,10-  .
MOA of drugs
Drugs that are commonly used as initial treatment for hypertensive emergency patients presented with ACS are glyceryl trinitrate(GTN), B-blocker, antiplatelet and anticoagulant agents. GTN causes arterial and venodilation which lowers the BP and reduces myocardial oxygen demand. In addition, it relieves coronary vasospasm and enhances myocardial oxygen delivery. Blockade on the B1 receptor in the myocardium by B-blocker lowers heart rate, contractility, BP and thus reduction of myocardial oxygen demand  ,  . At the same time, reducing the heart rate allows adequate ventricular filling improves coronary artery perfusion. B-blocker has also shown to reduce plasminogen activating inhibitor  . Antiplatelet agent such as aspirin is often used in the management of UA/NSTEMI. Aspirin induces antiplatelet effect by inhibiting the COX-1 pathway thus preventing the formation of thromboxane A2 which is an activator of platelet aggregation  . Low molecular weight heparin(LMWH) is also employed.
The goal of treatment is to reduce the BP progressively over minutes to hours. The acute treatment and choice of drugs usually depends on the affected organ system6,7. Hypertensive emergency patients presented with acute coronary syndrome usually required multiple drugs. Treatment needs to take into account all factors that lead to the pathogenesis of the disease such as increased in shear force, narrowing of coronary arteries, endothelial dysfunction and platelet activation that are associated with increased risk of morbidity and mortality in this group of patients13. It is recommended that BP should be reduced by 20-30% of baseline7,8,  .
Parenteral agents are ideal for treating hypertensive emergency as it is provides a rapid onset and offset, gives a maximal effects and dose is titratable to avoid hypotension3,9,18. Parenteral agents are gradually stepped down once the BP is controlled and oral agents are then introduced.
For management of hypertensive emergency in the setting of acute coronary syndrome, first line drugs that are recommended as treatment are IV glyceryl trinitrate(GTN) and B- blocker such as Labetalol, given by intravenous infusion3,9,18. Antiplatelet and anticoagulant therapy is also important in the acute management of this group of patients.
This essay is going to focus on the initial acute management of hypertensive emergency in the setting of acute coronary syndrome (Unstable angina/ NSTEMI).
Evidences for treatment and critical appraisal of the management plan
Nitroprusside and nitrates such as GTN are effective vasodilator indicated in hypertensive emergency. From the overview of 10 trials, both GTN and nitroprusside were found to reduce mortality by about 35% in patients with myocardial infarction (MI)  . For hypertensive emergency complicated with ACS, these agents have additional benefits by inhibiting the platelet aggregation which plays a role in the manifestation of ACS  ,  . In experimental animal model, GTN was implicated to have additional benefits by having a direct cardioprotective effect  ,  . Nitrates is recommended as drugs to be used in accordance to AHA and SIGN guidelines  [ AHA,SIGN].
GTN is usually preferred by physician over nitroprusside13for hypertensive emergency with coexistence of myocardial ischeamia as it provides a better coronary perfusion than nitroprusside, it is more superior in restoring the myocardial oxygen supply/demand effects  and has a favourable pulmonary gas exchange effects  than nitroprusside. In the study by Karlberg et.al.  , IV GTN proved to have reduced ischemic events such as MI in patients with unstable angina pectoris when compared to placebo.
On the other hand, the use of nitroprusside is often associated with thiocyanide toxicity especially in renal-impaired patients  ,  and it requires special handling due to its photodegradable property. These factors might act as limit for the use in hospital setting3.The dose of IV GTN is usually 5-10mcg/min and titrated up to 200mcg/min until reaching target BP by a continuous infusion. Treatment should be continued at least 24 hours after ischemic relief 14. Development of tolerance with prolonged use of IV GTN (24-48 hours) is an issue with the use of this drug. Therefore, IV GTN is usually given for 48 hours15.
In this patient, IV GTN infusion was given for more than 48 hours and tolerance may have developed which render the GTN ineffective.
B-blocker has shown to reduce the risk of recurrent ischemic, infarct size, mortality in the first week by 15% and it has a lesser occurrence of reinfarction in patients with acute myocardial infarction  .
In the context of management for hypertensive emergency complicated by myocardial ischemia, IV labetalol has proved to be effective in the initial treatment to achieve pre-determined BP goal at a gradual yet controlled manner  ,  . It is a Î±1 and Î² non-selective adrenergic receptor blocker. It is more advantageous than pure B-blocker such as reduces the peripheral vascular resistance without decreasing the cardiac output and therefore maintains the peripheral blood flow which is beneficial in myocardial ischemic patients  . Its long-acting action allows for easy conversion from IV to oral B-blocker. Labetalol has a rapid onset of action within minutes, the effects lasts for several hours. It may be given as an infusion of 1-2mg/min and increased gradually until the desired BP reduction is achieved. Incremental infusion has shown to be more effective and least prone to cause side effects than rapid injection and repeated bolus dose  . Preliminary evidence showed that IV labetalol has some effect in decreasing BP in patients with hemorrhagic stroke.
After the BP has been controlled for a suitable period, the IV agents should be waned off and replaced with oral agents. Meta analysis suggests the use of B-blocker in patients with UA/NSTEMI reduces the rates of progression to myocardial infarction by 13%  . The use of B-blocker after MI leads to reduction in mortality with metoprolol demonstrating the most pronounced beneficial effects compared to atenolol and propanolol  .
Antiplatlet therapy is fundamental in the management of UA/NSTEMI. Current guidelines recommend the use of aspirin, clopidogrel with or without glycoprotein IIB/IIIA receptor antagonist as antiplatelet therapy in UA/NSTEMI patients [AHA, SIGN]. Glycoprotein IIB/IIIA receptor antagonists is usually given to high risk UA/NSTEMI patients as additional antiplatelet therapy as documented by studies  . This patient was classified as low-risk group according to the GRACE risk score  , therefore the use of Glycoprotein IIB/IIIA receptor antagonists is not needed.
Aspirin has been used as one of the front-line drugs in patients presented with ACS as effectiveness of aspirin over placebo and its advantages was well documented  ,  ,  . Meta-analysis has demonstrated that aspirin lowers the incidence of vascular death, MI, stroke by a relative risk reduction of 46% compared to placebo in patients who has unstable angina. In the Second International Study of Infarct Survival (ISIS-2) trial41, aspirin was found to significantly lower the rate of non-fatal reinfarction and non-fatal stroke in patients with suspected acute MI. In addition, aspirin exhibits additional protective effect for UA patients against MI40,  However, the use of aspirin is often associated with increased risk of bleeding [antithrombotic, antiplatlet, SIGN, AHA]. In acute setting, aspirin dose of at least 150mg is normally required, however low-dose aspirin (75mg-150mg) is usually sufficient to use as maintenace therapy42. All these evidences prompt the recommendation to use aspirin (300mg then 75mg-150mg daily) in patients with ACS. In this patient, the use of aspirin was evidence-based and appropriate, however the patient should be monitored and signs of bleeding.
Clopidogrel, a thienopyradine derivatives acts by inhibiting platelet aggregation through its action on adenosine diphosphate. It appears to be a more effective antiplatelet than aspirin as demonstrated in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial  . Evidences from this trial showed that clopidogrel has a better outcome in reducing the risk of cardiovascular events and has a slightly better safety profile than aspirin.
The Clopidogrel in Unstable Angina to Prevent Recurrent ischemic Events (CURE) trial  highlighted the effects of addition of clopidogrel (300mg stat and 75mg daily) to aspirin as more beneficial in the initial management of patients presented with UA/NSTEMI regardless of whether revascularization is considered. 12,562 patients were randomised to receive either clopidogrel or placebo, both given together with aspirin. Combination of clopidogrel with aspirin was found to be more effective in decreasing cardiovascular death, MI and stroke compared to aspirin therapy alone (9.3% vs. 11.5%, p<0.001). A reduction in in-hospital refractory ischemia(8.7% Vs 9.3%) and recurrent angina(20.9% Vs 22.9%) were also noted with the use of clopidogrel. This was further supported by the outcomes in another trial where the combination of aspirin and clopidogrel demonstrated a modest benefit over aspirin in group of atherosclerotic patients with established vascular disease  . The benefit emerges within 24 hours after initiation of treatment44,  [Yusuf S,2003; Fox KAA].
However, the addition of clopidogrel to aspirin was associated with a higher risk of bleeding44,45. But the favourable clinical outcome for initiation of clopidogrel appears to outweigh the risks. From the case summary, it is evident that clopidogrel was not given to this patient, based on the vast evidences and the benefits or its use together with aspirin as initial treatment for UA/NSTEMI patient, it is recommended that clopidogrel 300mg to be initiated together with aspirin for the above hypertensive emergency patient presented to the emergency department.
Low Molecular Weight Heparin (LMWH)
LMWH is now the preferred choice of anticoagulant over unfractionated heparin (UFH) although both of them have similar effect in terms of mortality and major bleeding risk  ,48 . LMWH is more superior than UFH the risk of non-fatal MI and need for coronary revascularization procedures were lowered as demonstrated by the Cochrane review of seven randomised controlled trials  . The outcome of the TIMB 11B also shown similar results where there is a lower death occurrence and recurrent ischemic episodes  . The ease of administration, better safety profile due to less likelihood to cause thrombocytopenia than UFH  , longer half life thus enable twice daily dosing and the absence of need for continuous monitoring promotes the use of LMWH over UFH. LMWH such as enoxaparin is also more cost effective when compared with UFH  . However, it seems that enoxaparin is more likely to cause minor bleeding in patients.
On the other hand, synthetic pentasaccharides such as fondaparinux were shown to have an edge over LMWH. There appeared to be no significant difference between the risk reduction ischemic events between the use of these drugs. Nevertheless, OASIS-5 trial demonstrated that the use of fondaparinux is more superior than enoxaparin in terms of short and long-term mortality rate and bleeding risks  . A recent study showed that the use of fondaparinux is more cost-effective than enoxaparin to be used as an antithrombotic in UA/NSTEMI  .
With reference to the case summary, MR ABC was given enoxaparin as antithrobotic agents during his stay in the hospital. Based on the clinical evidences, fondaparinux appears to be a more favourable choice in terms of its safety profile and cost effectiveness. The recommended dose or fondaparinux is 2.5mg daily  .
It is important to 'treat the patients and not just the number'7[medscape- McCowen], which means management of such patients should not solely depends on lowering the BP but at the same time to treat the complications that come with this emergency and to reduce the overall CVD risk of the patients using multidisciplinary approaches. Antihypertensive drugs such as angiotensin-Converting-Enzyme (ACE) inhibitor, with addition of other anti-ischemic, antiplatelet agents, anticoagulants, lipid-lowering agents are important as the overall management of hypertensive emergency patient presented with acute coronary syndrome. Secondary prevention of future CVD events should not be ignored as part of the management of this group of patients.
Overall, there is not much large scale randomised controlled trials devoted to assess the hypertensive emergency therapy  compared to the vast amount of resources and clinically based evidences that are available for the treatment of chronic hypertension. In light of this, more clinically significant randomised controlled trials such as comparing the efficacy of drugs used are needed for a better evidence-based management of hypertensive emergency. However, because of ethical reason and low incidence of such events, these clinically important data are unlikely to be acquired. Therefore, long-term management of hypertension to achieve an optimal BP is more important as a preventative measures for occurrence of such events and other complications related to high blood pressure.