How soon before cardiac surgery should aspirin be stopped?

How soon before cardiac surgery should aspirin be stopped?

Aspirin irreversibly inhibits platelet function by blocking the cyclooxygenase pathway. It is a vital adjunct in the prevention of coronary thrombosis and is known to reduce the risk of acute bypass graft closure. Unfortunately it also causes increased bleeding after cardiac surgery and increases the risk of emergency re-sternotomy in the first few hours. For this reason many centres try to stop aspirin for a few days prior to surgery.

Platelets have a life span in the plasma of approximately 10 days. Therefore if aspirin were discontinued 10 days prior to surgery, the affected platelet pool would be completely replenished with fresh platelets by the time of the operation. This however leaves the patient vulnerable to an acute myocardial event during the latter part of this time and may also make graft occlusion more likely in the immediate postoperative period. It also supposes that operating lists can be planned 10 days in advance.

In reality, patients are usually asked to stop aspirin 5-7 days in advance. This seems to be a suitable compromise for the majority of patients although for a few (tight left main stem stenosis or past history of TIAs or stroke), the risk of stopping aspirin may outweigh the potential benefits.

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How does recent myocardial infarction affect the perioperative risks of coronary artery bypass grafting?

How does recent myocardial infarction affect the perioperative risks of coronary artery bypass grafting?

Common sense suggests that the more recent the infarction, the higher the operative risk. This is because the infarcted area is surrounded by a critically ischaemic zone. The ultimate survival of this zone depends on many factors, not least of which is the global function of the remaining myocardium. This function is temporarily further compromised by the process of cardiopulmonary bypass for coronary artery surgery. The likely outcome during this critical phase, therefore, is extension of the infarcted area, with obvious implications for survival of the patient.

It is the duration of this critical phase which is most in doubt. In a recent small retrospective analysis, Herlitz et al1 found that amongst patients with a history of myocardial infarction, infarction within 30 days of surgery was not an independent predictor of total mortality within 2 years of surgery. However, Braxton et al made a distinction between Q wave and non-Q wave infarctions in the perioperative period. Although both types rendered the use of balloon pumps and inotropes to wean from bypass more likely, only Q wave infarctions were associated with significantly increased surgical mortality and even then only if surgery was performed within 48 hours of the infarction.

An older but much larger series from Floten et al seems to support a high risk for the initial 24-48 hours or so, but more importantly emphasises the relationship between the number of diseased vessels and the risk of surgery after recent infarction. Applebaum et al found ejection fraction less than 30%, cardiogenic shock and age greater than 70 years to be significant determinants of death in patients operated upon within 30 days of infarction. These are not surprising factors, fitting as they do with the concept that it is the extent of the jeopardised myocardium which is the determinant of risk, especially within the first day or two after the myocardial infarction.

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Are there benefits to switching from sulphonylureas to insulin after coronary artery bypass grafting?

Are there benefits to switching from sulphonylureas to insulin after coronary artery bypass grafting?

Sulphonylureas help to control blood glucose levels by binding to adenosine-5-triphosphate(ATP)-sensitive potassium channels (K_ATP-channels) in the beta-cells of the pancreas. This inhibits potassium flux across the cell membrane, leading to depolarisation of the plasmalemma and subsequently the release of endogenous insulin. These same K_ATP-channels are also found in the myocardium and in vascular smooth muscle cells and are therefore implicated in the regulation of the cardiovascular system.

A fall in myocardial cytosolic levels of ATP and a rise in extracellular adenosine opens the K_ATP-channels during myocardial ischaemia. This is thought to be a natural protective action, related to the phenomena of preconditioning and hibernation. Glibenclamide abolishes this effect at clinically relevant doses and infarct size is increased in animal models of myocardial ischaemia. These drugs also antagonise the vasodilating effects of drugs like minoxidil and diazoxide and can reduce resting myocardial blood flow. In contrast, sulphonylureas might reduce the incidence of post-ischaemic ventricular arrhythmias. By blocking K_ATP-channels, they prevent the tendency towards shortening of the action potential during myocardial ischaemia secondary to potassium efflux through opened channels.

Secondly, since type II diabetics are both insulin deficient and insulin resistant, glycaemic control may be improved in some individuals by combining oral medication with insulin or by switching completely.

In summary there remain theoretical arguments for and against changing from sulphonylureas following coronary surgery. The position may be eased by the development of more pancreas-specific drugs. For the time being at least, strict glycaemic control by whatever means should remain the primary aim, if necessary using short acting, low dose sulphonylurea derivatives.

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How common are neuropsychological complications after cardiopulmonary bypass (CPB)? How predictable and severe are they? Can they be prevented?

How common are neuropsychological complications after cardiopulmonary bypass CPB)? How predictable and severe are they?Can they be prevented?

Neuropsychological complications have been found to occur in a proportion of patients following CPB. These problems reveal themselves as impaired cognitive function, i.e. difficulties with memory, attention, concentration, and speed of motor and mental response. However, the reported frequency with which these problems occur varies considerably. Studies assessing patients 5-10 days postoperatively have suggested an incidence of neuropsychological deficits ranging from 12.5 to 90%. Later assessments, at about 2 to 6 months after surgery, have indicated deficits in 12 to 37% of patients studied.

How predictable are they?

The variation in reported incidence has been ascribed to several factors such as number, type, sensitivity, and timing of neuropsychological tests used, as well as the definition of neuropsychological deficit and the method of statistical analysis employed. These methodological issues have been addressed at international consensus conferences in 1994 and 1997. Patient related variables such as age and disease severity have also been associated with cognitive decline post-cardiac surgery. Therefore centres employing different criteria for surgery may report differing rates of deficit.
Deficits detected within a few days of surgery are also problematic in that they are often transient in nature. These assessments appear to be contaminated by postoperative readjustment and anaesthetic residue as well as genuine neuropsychological difficulties. Long term deficits (over 6 weeks) are considered to be more stable and to reflect a more persistent neuropsychological problem.

How severe are they?

Given that these problems reflect a decline in performance of approximately 20-25% from that prior to surgery, they can be considered severe. What is more difficult is how they translate into the patient’s everyday life. This is dependent upon the nature of their activities. A cardiac surgeon who suffered a 20% decline in their fine motor movements would undoubtedly have a severe disability. In contrast a road sweeper would not suffer unduly, at least in their work. The tests customarily performed in this area are most useful as a window onto surgery rather than showing an impact on quality of life.

Can they be prevented?

The mechanisms for neuropsychological decline are considered to be multifactorial. The most popular explanation for cognitive dysfunction is microemboli delivered to the brain during surgery. These can be either air or particulate (atheromatous matter, fat, platelet aggregates, etc.) in nature. In an attempt to reduce the incidence of neuropsychological decline various interventional studies have been designed. Much of this work has centred on the impact of different equipment and techniques used in surgery on neuropsychological outcome. Early studies comparing bubble and membrane oxygenators indicated a higher frequency of microemboli detected when using bubble oxygenators with decreased neuropsychological deficits occurring in the membrane group. Studies have also found that the introduction of an arterial line filter into the CPB circuit significantly reduces the number of microemboli detected at the middle cerebral artery during CABG. A significant reduction in neuropsychological deficits in the filter group has also been reported. In contrast a study comparing pulsatile and non-pulsatile flow found no difference in neuropsychological outcome between the two techniques.

As the use of hypothermic perfusion during CPB has been based on the protective effects of low temperature in limiting the effects of cerebral ischaemia it is surprising that studies so far have failed to find any advantage for hypothermic bypass on neuropsychological outcome. Two studies have examined the impact of pH management on cognitive performance and both have reported benefit from using the alpha stat technique. Less disruption to autoregulation has also been reported in the alpha stat group.

More recently pharmacological neuroprotection has been attempted in these patients with a variety of compounds. Most of these studies have been underpowered and only one appears to have produced some suggestion of neuroprotection.

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Coronary artery bypass grafting: what is the case for total arterial revascularisation?

Coronary artery bypass grafting: what is the case for total arterial revascularisation?

The clinical and prognostic benefits of coronary artery bypass grafting (CABG) for certain subgroups of patients with ischaemic heart disease are well established. Most patients have three vessel coronary artery disease and the conventional CABG operation uses a single internal mammary artery (IMA) and two vein grafts to perform three bypass grafts. This procedure provides excellent short and intermediate term outcome but is limited, in the long term, by vein graft failure. Ten years after CABG 95% of IMA grafts are patent and disease free whereas three quarters of vein grafts are severely diseased or blocked.

The case for one arterial graft

For over a decade the superior patency of a single IMA over vein grafts has been known to improve survival and to reduce the incidence of late myocardial infarction, recurrent angina and the need for further cardiac interventions.

The case for two arterial grafts

Substantial evidence for the prognostic and clinical benefits of both IMA grafts has recently been reported in a large study from the Cleveland clinic. In comparison to the use of a single IMA graft, use of both IMA grafts resulted in a further significant improvement in survival (with a reduction in mortality by 10% at 10 years) and a fourfold reduction in the need for reoperation. Furthermore, these benefits extended across all groups of patients with a five year life expectancy including "elderly" patients (up to mid-seventies), and those with diabetes and impaired ventricular function. The major concern of harvesting both IMA is an increase in sternal wound complications. This can be avoided by a skeletonisation rather than a pedicled technique which leaves collateral vessels intact on the sternum and allows the safe use of both IMAs even in diabetic patients.

The case for three arterial grafts

Several arteries have been proposed as the third arterial graft and the most widely used is the radial artery. The radial artery is a versatile conduit, which can be harvested easily and safely, has handling characteristics superior to those of other arterial grafts and comfortably reaches any coronary target. For the patient it offers the prospect of superior graft patency compared to saphenous vein grafts4 as well as improved wound healing. The potential impact of the radial artery on survival is not yet established as it has only been in widespread use for five years.
Finally, many patients are interested to know "how long grafts are likely to last". This may be viewed most helpfully in terms of event rates, rather than physical lack of occlusion of a graft: "ischaemic event rate" (5% per year) and cardiac mortality (2-2.5% per year). A recurrent "event" (death, MI or recurrence of angina) occurs in 25% of surgically treated patients in <5 years, and 50% at 10 years.

In summary, the use of arterial grafts offers substantial short and long term clinical and prognostic benefits. In particular the use of both IMA grafts significantly reduces mortality and the need for re-operation. Current evidence suggests that the superior patency of arterial grafts also reduces perioperative mortality by reducing perioperative myocardial infarction. This is particularly true in patients with smaller or more severely diseased coronary arteries (females, diabetics, Asian background) where discrepancy between the size of vein grafts and coronary vessels leads to "runoff" problems and a predisposition to graft thrombosis. Careful harvesting of both IMAs can be performed even in diabetic patients without an increase in wound healing problems. Relative contraindications to arterial grafts are patients who are likely to require significant inotropic support in the postoperative period (because of the risk of graft vasoconstriction) or those with severely impaired ventricular function (ejection fraction less than 25%) and limited life expectancy.

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What patterns of coronary disease are associated with improved short and long term survival after CABG compared with medical therapy?

What patterns of coronary disease are associated with improved short and long term survival after CABG compared with medical therapy?

Many factors have influenced the short and long term results of bypass surgery, not least the improvements in surgical techniques and experience, changes in the population of patients undergoing surgery, many of whom would never have been deemed suitable for surgery even 10 years ago, improvements in postoperative medical management and the use of the left internal mammary artery (LIMA) as the graft of choice for the left anterior descending coronary artery (LAD) in virtually all patients today.

30 day operative mortality

Short term survival after bypass surgery is 1-3% at most institutions around the world. The Society of Thoracic Surgeons National Database mortality figures1 for 80,881 patients undergoing isolated bypass surgery between 1980 and 1990 were 4.75% for left main disease, 3.32% for triple vessel disease and 2.86% for one and two vessel disease. In-hospital mortality was 2.9% for first time operation and 7.14% for re-operation. Recognised factors affecting in-hospital mortality include older age, female sex, co-morbid renal and cardiovascular disease, diabetes, cardiogenic shock, emergency, salvage or redo operation, preoperative intra-aortic balloon pump use and associated valve disease.

Long term survival after surgery

The late results of bypass surgery depend on the extent of cardiac disease, the effectiveness of the original operation, progression rate of atherosclerosis and the impact of non-cardiac disease. Patient-related variables associated with poorer late survival include reduced ventricular function, congestive cardiac failure, triple vessel or left main stem disease, severity of symptoms, advanced age and diabetes.
The patients who gain most from surgery are those most at risk from dying with medical therapy alone. Pertinent high-risk characteristics included left main stem (LMS) disease, triple vessel disease or double vessel disease that included a proximal LAD lesion, and triple vessel disease associated with impaired LV function. The VA study at 18 years demonstrated superior surgical survival throughout the 18 years, but was only significant overall at 7 years (med. vs surg. survival 53% vs 79% p = 0.007); benefit was much greater in the high risk group with LMS stenosis >50%, single or double vessel disease with impaired LV function, and triple vessel disease with LV EF <40%. In 1988 ECSS reported 12 year results demonstrating significantly higher cumulative survival in the surgical group, notably again in patients with 3 vessel disease (med. vs surg. survival 82% vs 94% (p = 0.0002) at 5 years and 68% vs 78% (p = 0.01) at 10 years). Proximal LAD disease >95% in two or three vessel disease was an outstanding anatomical predictor of survival (med. vs surg. survival at 10 years 65% vs 77% (p = 0.007)), again with significant crossover into the surgery group. The CASS study demonstrated no difference in survival for any subset at 5 years, but did not include any patients with poor LV function, LMS disease, angina greater than class 2, co-morbid disease or unstable angina. It is therefore difficult to extrapolate data from this trial to modern patient populations.
Combining results from seven of these early randomised trials led to the publication of survival figures for 5, 7 and 10 years. Medical vs surgical mortality for all patients was 15.8% vs 10.2% (p = 0.0001) at 5 years, with attenuation of this benefit to a mortality of 30.5% (med.) and 26.4% (surg.) (p = 0.03) at 10 years. Extension of life for all patients having surgery was 4.3 months at 10 years. High-risk patients once again benefited the most from surgery, but in lower risk groups, a survival extension for those with proximal LAD disease (14 months), triple vessel disease (7 months) or LMS disease (19 months) was identified. This survival benefit was independent of degree of LV impairment or abnormal stress testing. Median survival for patients with LMS disease was 13.1 years in the surgical group and 6.2 years for those treated medically. The superior patency of the LIMA graft compared with saphenous vein grafts has been established beyond any doubt and additional survival benefit, up to 18 years, has been demonstrated.

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Which patients with post-infarct septal rupture should be treated surgically, and what are the success rates?

Which patients with post-infarct septal rupture should be treated surgically, and what are the success rates?

Myocardial rupture is a more common cause of death after infarction than is generally appreciated. It complicates about 3% of all myocardial infarctions and is the cause of death in about 17% of fatal infarcts. Myocardial rupture can involve the LV wall, the septum and the papillary muscles and occurs in proportion to the amount of muscle at risk with a ratio of about 10:2:1. Rupture of the LV wall is almost always immediately fatal and is the cause of death in about 13% (75% of 17%) of all fatal infarcts, as "electromechanical dissociation".
The minority who rupture only through the septum (loosely known as post-infarct VSD) may be saved by surgery. The hospital mortality for surgical repair is probably 40% (without reporting bias - but there is surgical selection and natural selection - most have had to survive transfer to a surgical centre). The mortality is close to 100% without surgery. Favourable features are younger age, anterior rather than inferior infarcts, more surviving left and right ventricular myocardium, and functioning kidneys. There was a vogue for holding these patients on a balloon pump to operate on them when the infarcted tissue is better able to take stitches. It is a long wait before there is any material advantage, and any benefit in reported figures of percentage operative survival was due to loss of patients along the way. If you are going to operate on these cases, it is probably a case of the sooner the better.
Current data would suggest that concomitant coronary artery bypass grafting does little to improve mortality rates from surgical post-infarct VSD.

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What is the risk of patient dying or having a myocardial infarction around the time of surgery for coronary artery disease and for valve replacement?

What is the risk of a patient dying or having a myocardial infarction around the time of surgery for coronary artery disease and for valve replacement?

General approach to quoting numbers
First some general comments. The figures given should ideally be those currently being achieved by the team to whom the patient is referred. In general terms, registry data are more representative than published series, which inevitably include bias towards more successful figures. The data should be adjusted up or down to match the circumstances of the individual patient, who is helped towards a rational decision based on the anticipated risks and benefits.

What is the risk of death with CABG

The UK Cardiac Surgery Register for the three years up to 1997 gives a 3% mortality for isolated coronary artery surgery, which is applicable to the current case mix. It therefore applies to the typical patients - male, elective, aged 60-70, with an adequate left ventricle. Patients with one or more risk factors for perioperative death, which are older age, female sex, obesity, worse ventricular function, diabetes, very unstable or emergency status, or significant co-morbidity of any type, should have the stated risk appropriately increased.

What is the risk of death with valve replacement?

The United Kingdom Heart Valve Registry provides very reliable thirty day mortality figures which for the three years 1994-1996 inclusive were 5% for aortic valve replacement and 6% for mitral valve replacement.

What is the risk of stroke?

Lethal brain damage and permanently disabling hemiplegia are rare with a combined risk of about 0.5% in current practice. If every focal deficit discovered on brain imaging, or every transient neurological sign is included the incidence would probably be nearer 5%. Most of these focal deficits are caused by atheroembolism. Air, left atrial thrombus and calcific valve debris are additional risk in valve surgery. I quote the routine patient a risk of stroke of 1% to 2% adjusted upwards for increasing age, history of previous stroke or TIA, and hypertension, and adjusted down for relative youth. The incidence of subtle diffuse or global brain injury depends on definition. Some difficulty with concentration and memory affects about a quarter of patients - but very few are troubled by it to any extent.

What is the risk of myocardial infarction?

This is extremely difficult to define. In good hands it rarely complicates valve operations without coronary artery disease. In coronary surgery incidence depends on definition but myocardial dysfunction, local or global, is the commonest cause of death. The incidence of infarction is entirely dependant on definition and any figure from 2% to 10% could be given, depending on the criteria used.

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What is the mortality rate for cardiogenic shock complicating myocardial infarction?

What is the mortality rate for cardiogenic shock complicating myocardial infarction? How should such patients be managed to improve outcome and what are the results?

The advent of the thrombolytic era has not altered the incidence or mortality rate for cardiogenic shock complicating myocardial infarction (MI). It still represents almost 10% of patients with MI, with almost 90% dying within 30 days.
Pooled results from retrospective, unrandomised data or historical reviews, which examined the effects of early revascularisation, have suggested reduced mortality following bypass surgery (CABG) or coronary angioplasty (PTCA) to 33% and 42% respectively. Recently, a few randomised trials have attempted to compare such early (within 48 hours) revascularisation with a strategy of initial medical stabilisation. The latter might include thrombolysis, inotropic support and intra-aortic balloon pump counterpulsation (IABP), still with the option of delayed intervention. It is unfortunate that most of these studies have faltered on slow patient recruitment leaving only one completed study (SHOCK,SHould we emergently revascularise Occluded Coronaries for Shock) to guide our management of these patients.
Over a 5 year period, the SHOCK trial randomised 302 patients to receive either early revascularisation within hours from randomisation, or initial medical stabilisation with the option of delayed intervention. Thirty day mortality was reducedin the early intervention group (46% vs 56%) with this benefit extending out to 6 months and particularly apparent in the younger (<75 years) age group. The low mortality in the control group is striking, and explains the lack of a large difference between the two groups. Nevertheless, it suggests benefit even with a relatively aggressive conservative policy in these patients.
Because of trial recruitment difficulties it is unlikely that further randomised data will emerge in the foreseeable future. Evidence from the SHOCK trial would seem to suggest that at present it would be reasonable to consider an aggressive approach with early revascularisation in patients with shock complicating myocardial infarction. However, access to surgery should be available - 36% of patients required this intervention rather than PTCA. Mean time to revascularisation was under 1 hour in the trial, and quite how much later such benefit might extend is unclear. Care should include vigorous medical stabilisation in all such patients with thrombolysis, inotropes, balloon pumping and even ventilation if necessary with a view to late revascularisation (PTCA or CABG). In young patients early (<48 hours)
revascularisation should be considered.

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What advice should I give patients about driving and flying after myocardial infarction?

What advice should I give patients about driving and flying after myocardial infarction?

Compared to other forms of international travel, flying presents fewer demands on the invalid passenger than the alternative modes of travel. Airlines have a duty of care to other passengers who may be inconvenienced by emergency diversions, unscheduled stops and delays in the event of a medical emergency.
Recertification of drivers and pilots following myocardial infarction depends upon their subsequent risk of incapacitation whilst at the controls. All pilots and all professional drivers have a duty to inform the relevant licencing authority as soon as possible following myocardial infarction.
There are no international regulations governing the prospective passenger who has recently suffered a myocardial infarction and no statutory duty to inform the airline concerned. Most will be guided in the decision whether to fly or not by their cardiologist or family doctor. Modern passenger aircraft have a cabin atmospheric pressure equivalent to 5-8,000 feet, and alveolar oxygen tension falls by around 30%. This may exacerbate symptoms in any patient who experiences angina or shortness of breath whilst walking 50 metres or climbing 10 stairs. The enforced immobility of the passenger on a long flight, airport transfers and the crossing of time zones should be considered.
If fewer than 10 days have elapsed since myocardial infarction, or if there is significant cardiac failure, angina or arrhythmia the patient may require oxygen or suitable accompaniment. The airline should be informed, and will request a report on a standard medical information form (MEDIF).
Professional pilots are disqualified from flying for nine months after myocardial infarction, but may subsequently be allowed to fly in a multi-pilot aircraft provided that investigations, carried out by a cardiologist acceptable to the licencing authority, are satisfactory, as follows:

• Exercise ECG to Bruce protocol stage 4 reveals no evidence of ischaemia
• 24 hr ECG reveals no abnormality
• Echocardiogram shows ejection fraction greater than or equal to 50% and normal wall motion
• Coronary angiography reveals no stenosis greater than 30% in any vessel distant from the infarction
• Any underlying risk factors must have been appropriately treated, and certification will be subject to annual cardiology review, with further coronary angiography within 5 years.

Private pilots are subject to the same regulations but may fly with a suitably qualified safety pilot in a dual control aircraft without undergoing angiography. Symptomatic or treated angina, arrhythmia or cardiac failure disqualifies any pilot from flying.
Professional drivers may be relicenced 3 months after myocardial infarction provided that there is no angina, peripheral vascular disease or heart failure. Arrhythmia, if present, must not have caused symptoms within the last 2 years. Treatment is allowed provided that it causes no symptoms likely to impair performance.

• Exercise ECG to Bruce protocol stage 3 must reveal no symptoms or signs of ischaemia.
• Recertification will be subject to periodic satisfactory medical reports.

Private drivers need not inform the licencing authority after myocardial infarction, but should not drive for one month. If arrhythmia causes symptoms likely to affect performance, or if angina occurs whilst driving, the licencing authority must be informed, and driving must cease until symptoms are adequately controlled.

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What is appropriate secondary prevention after acute myocardial infarction?

What is appropriate secondary prevention after acute myocardial infarction?

At least half the patients who suffer an acute infarct will survive at least one month, though 10-20% will die within the next year. It is to be hoped and expected that more active early intervention will bring about further improvements in short term survival. There is therefore a large and growing number of patients where there is a need to prevent further cardiovascular events and to maintain and improve the quality of life.

Aspirin

Aspirin at low to medium doses (75-325mg daily) reduces mortality, reinfarction and particularly stroke by 10-45% after myocardial infarction. It has been estimated that there is about one serious haemorrhage, gastrointestinal or intracerebral, for every event prevented. At the moment there is no comparable evidence for dipyridamole, ticlopidine or clopidogrel.
Beta blockers
There is overwhelming evidence for the beneficial effect of beta blockers, both within the first few hours of myocardial infarction and for up to three years afterwards. Reduction in mortality ranges from 15 to 45%, almost all of it accounted for by fewer instances of sudden death. All beta blockers appear equally suitable, except those with partial agonist activity. The contraindications are controversial, but most would include asthma, severe heart block and otherwise untreated heart failure, but patients with poor left ventricular function benefit most. In asthmatic patients, particularly, heart rate limiting calcium channel blockers (verapamil or diltiazem) may be useful alternatives to beta blockers in the absence of uncontrolled heart failure.

Lipid-lowering drugs

The large secondary prevention trials with simvastatin and pravastatin (4S, CARE, LIPID) have demonstrated unequivocally the value of cholesterol lowering even in patients with "average" total LDL cholesterol levels of about 5mmol/l. It is arguable that any patient who has had a myocardial infarct should be offered treatment with a statin on the basis that their level of LDL cholesterol is too high for them. However, this is not orthodox practice at present. The previous practice of only measuring cholesterol levels some months after an infarct should be abandoned and the levels assayed on admission at the same time as cardiac enzymes. This gives a reliable figure for usual cholesterol levels: a delay of a couple of days in sampling will not. Following the VA-HIT study treating patients with HDL cholesterol levels 1 mmol/l with a fibrate should be considered but again is not yet established practice.

ACE inhibitors

These drugs would of course be used in patients with symptomatic heart failure but should also be used in asymptomatic patients with ejection fractions <40%. This is associated with significant decreases in mortality (20-30%) and in sudden death, as well as in reinfarction. All ACE inhibitors so far tested share these effects. Treatment should be started within 1-2 days of the infarct and should be continued indefinitely. Whether all patients should be given these drugs post-infarction, in the absence of contraindications, is a more difficult issue. In unselected populations the benefits of treatment are much less clear cut. However, data from the recent HOPE trial suggest substantial risk reduction for higher risk vascular patients - which may include a large proportion of patients who have suffered a myocardial infarction. Other ongoing trials (such as EUROPA, using Perindopril) may help clarify this issue.

Other action

In addition to these relatively specific measures, diabetes and hypertension must of course be treated as required, and smoking discouraged. Some have advocated the use of fish oils especially in dyslipidaemic patients, either as supplements or as fish. The use of warfarin has been controversial for many years. It is highly effective in preventing cardiovascular events, particularly stroke, but at the cost of more adverse effects than aspirin and the inconvenience of monitoring. It is therefore not recommended for first-line use by most cardiologists.

Finally, it should be remembered that all of this translates into a considerable burden for our patients. Evidence-based medicine will lead to the prescription of 4 or more drugs, usually indefinitely. We must be prepared to make a case for the patient to accept that it really is worthwhile. At the moment, for whatever reasons, most of these proven measures are underused.

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What are the risks of recurrent ischaemic events after myocardial infarction?

What are the risks of recurrent ischaemic events after myocardial infarction: prehospital, at 30 days and at 1 year?

Data from the WHO MONICA project in 38 populations from 21 countries show that 49% and 54%, respectively, of all men and women with an acute coronary event die within 28 days. About 70% of these deaths occur out of hospital on day 1 and it is generally accepted that a large proportion of these early deaths are the result of ventricular fibrillation. Thus provision of rapid access to a defibrillator remains the single most effective way to save lives in acute coronary syndromes. Following hospital admission the outcome of acute myocardial infarction is determined largely by left ventricular function. Before the introduction of thrombolytic and other reperfusion strategies, average in-hospital mortality from acute myocardial infarction declined from 32% during the 1960s to 18% during the 1980s. With the introduction of reperfusion therapy further improvements in the short and long term prognosis of acute myocardial infarction have been confirmed in several large studies comparing cohorts of patients admitted before and after the late 1980s. Thus, in a group of patients who received CCU treatment for acute myocardial infarction, we reported 30 day and 1 year mortality rates (95% confidence intervals) of 16.0% (13.4-19.2%) and 21.7% (18.6-25.2%), rising to 19.6% (16.6-23.0%) and 33.2% (29.5-37.2%), respectively, when a combined end point of mortality plus non-fatal recurrent events (unstable angina, myocardial infarction) was considered. Multivariate predictors of better short term survival included treatment with thrombolysis and aspirin, while predictors of worse survival included left ventricular failure, advanced age and bundle branch block. Whether survival after acute myocardial infarction has continued to improve in the thrombolytic era is unknown although the increasing application of effective secondary prevention strategies provides grounds for optimism.

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Exercise testing after myocardial infarction: how soon, what protocol, how should results be acted upon?

Exercise testing after myocardial infarction:how soon, what protocol, how should results be acted upon?

Risk stratification in acute myocardial infarction aims to identify patients at greatest risk of recurrent ischaemic events who might benefit prognostically from further investigation and treatment. Risk, however, is not a linear function of time, more than 60% of all major events during the first year occurring in the first 30 days after hospital admission. Recognition of this fact has rendered obsolete old arguments about the appropriate timing of stress testing and other non-invasive tests which must be performed as early as possible (certainly before discharge) to be of significant value. Not all patients need a stress test, which is unlikely to provide significant incremental information when unrelieved chest pain or severe heart failure, for example, confirm a high level of risk.
However, there remains a group that makes a largely uncomplicated early recovery for whom pre-discharge stress testing is recommended as a means of detecting residual myocardial ischaemia. A symptom limited test using the Bruce protocol is recommended for most patients although for some, particularly the elderly, modified protocols may be more suitable. An abnormal stress test with regional ST depression may be predictive of recurrent ischaemic events and provides grounds for coronary arteriography with a view to revascularisation. Other markers of risk include low exercise tolerance (<7 mets), failure of the blood pressure to rise normally during exercise and exertional arrhythmias. Unfortunately, recent meta-analysis has shown that inducible ischaemia during treadmill testing has a low positive predictive value for death and myocardial infarction in the first year, falling below 10% in patients who have received thrombolytic therapy. Nevertheless, when "non-ischaemic" risk criteria are considered, the treadmill may provide added clinical value, inability to perform a stress test and low exercise tolerance both being independently predictive of recurrent events.
Moreover, the negative predictive accuracy of pre-discharge stress testing is high, those with a normal test usually having a good prognosis without need for additional investigation. Finally, it should be noted that the diagnostic value of exertional ST depression and reversible thallium perfusion defects is equivalent, making the treadmill a more cost effective strategy for risk stratification than the gamma camera.

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What are the contraindications to thrombolytic therapy for acute myocardial infarction? Is diabetic retinopathy a contraindication?

What are the contraindications to thrombolytic therapy for acute myocardial infarction? Is diabetic retinopathy a contraindication?

Haemorrhagic complications (particularly intracranial) are the most important risks associated with thrombolysis. The 1996 ACC/AHA guidelines for the management of acute myocardial infarction list four absolute contraindications to thrombolytic therapy:
• Previous haemorrhagic stroke or other stroke within one year
• Known intracranial neoplasm
• Active internal bleeding (excluding menses)
• Suspected aortic dissection.
In cases where the nature of the stroke (haemorrhagic or otherwise) is unknown, then the risk of not administering a thrombolytic agent should be considered. The majority of strokes are occlusive in origin, and thus lack of certain knowledge should probably not represent a contraindication to thrombolysis in those patients (such as those with extensive territories of myocardial infarction who present early) who have most to gain.
In addition, there are relative contraindications for which the potential risks need to be assessed against the anticipated benefits:
• Uncontrolled hypertension or history of chronic severe hypertension
• Known bleeding diathesis or anticoagulant therapy with INR 2-3
• Trauma or internal bleeding (within 2-4 weeks), major surgery(<3>10 minutes), non-compressible vascular puncture, active peptic ulcer
• Pregnancy
• For streptokinase/anistreplase - prior exposure (with 5 days to 2 years) or prior allergic reaction.
Ocular haemorrhage after thrombolysis has been reported, and diabetic retinopathy was once considered a relative contraindication to thrombolytic therapy in AHA/ACC guidelines.Although no systematic evaluation has been performed, the GUSTO-I trial observed no intraocular haemorrhages in 6011 patients with diabetes. Currently, therefore, diabetic retinopathy is only considered a contraindication to thrombolysis if there is clear evidence of recent retinal haemorrhage.

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Is angioplasty better than thrombolysis in myocardial infarction? Which patients should receive primary or "hot" angioplasty for these conditions?

Is angioplasty better than thrombolysis in myocardial infarction? Which patients should receive primary or “hot” angioplasty for these conditions?

In patients with ST elevation myocardial infarction (MI) there is impressive evidence that primary percutaneous transluminal coronary angioplasty (PTCA) results in lower morbidity and mortality than does intravenous thrombolysis. This was first demonstrated in the Primary Angioplasty in Myocardial Infarction (PAMI) trial where primary PTCA resulted in a significant reduction in in-hospital and 6 month composite of death plus non-fatal recurrent myocardial infarction. There was also a significant reduction in intracranial bleeding with primary PTCA. The GUSTO IIb angioplasty substudy also showed a significant reduction in the combined end point of death, nonfatal reinfarction or disabling stroke at 30 days. A recent metaanalysis of 10 trials comparing primary PTCA to intravenous thrombolytic therapy showed a 34% reduction in mortality (p = 0.02), a 65% reduction in total stroke (p = 0.007) and a 91% decrease in haemorrhagic stroke (p < 0.001) among patients undergoing primary PTCA. In addition, PTCA has been shown to be superior to intravenous thrombolytic therapy in acute MI patients with cardiogenic shock, congestive heart failure, prior coronary bypass surgery (where the culprit vessel is often a thrombosed saphenous vein graft) and in nearly all patients in whom thrombolytic therapy is contraindicated. However, data suggest that the success of primary intervention is dependent on the frequency with which the procedure is performed. In addition, there are cost implications to providing such a service which, in any event, is unlikely to become available in every Western hospital.

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Treating acute Myocardial Infarction

Which thrombolytics are currently available for treating acute myocardial infarction? Who should
receive which one? What newer agents are there?

Thrombolysis

Natural thrombolysis occurs via the action of plasmin on fibrin thrombi. Plasmin is formed from plasminogen by cleavage of a single peptide bond. Plasmin is a non-specific protease and dissolves coagulation factors as well as fibrin clots. Three thrombolytic agents are currently available. Streptokinase (SK) forms a non-covalent link with plasminogen. The resultant conformational change exposes the active site on plasminogen to induce the formation of plasmin. Tissue plasminogen activator (tPA) is a serine protease and binds directly to fibrin via a lysine site, activating fibrin-bound plasminogen. The theoretical advantages of tPA are its increased specificity and potency because of its direct effect on fibrin-bound plasminogen. Being the product of recombinant DNA technology, there should be no allergic reaction to tPA. Unlike SK which should be used only once, tPA can be used repeatedly. Some, but not all, of these theoretical advantages translate into definite clinical benefit. Recently reteplase, a variation of tPA, has become available.
The Fibrinolytic Therapy Trialists Collaborative Group summarised results from thrombolytic trials encompassing more than 100,000 patients. The overall relative risk reduction in 35 day mortality with treatment was 18% (p < 0.00001). The mortality at this time was ~13%, reduced to 8-9% with treatment. However, in real life where the population is older than in the trials the true mortality is about 18-20%. Administration of a thrombolytic saves about 30 lives in a 1000 in those presenting within 6 hours of symptom onset but only 20 lives in a 1000 when patients receive treatment between 6 and 12 hours after symptom onset. Aspirin has an independent beneficial effect on mortality and can be chewed. The LATE Trial showed no benefit 12 hours after onset of symptoms. Judging the onset of symptoms can be difficult and may be influenced by collateral flow from another artery. If a patient presents with stuttering symptoms over 24 hours or so but has had severe pain over a few hours and has an appropriately abnormal ECG, thrombolytic treatment should be seriously considered. Prehospital thrombolysis has been shown to reduce cardiac mortality compared to in-hospital thrombolysis by 17% (p = 0.03), by reducing the mean time to treatment by about one hour.4 Despite this, prehospital thrombolysis has in general not been taken up for logistical reasons.

Is one thrombolytic better than another?

Although angiographic studies show higher early patency rates with tPA compared with SK (~70% vs ~35%), neither the GISSI- 2 study5 nor the ISIS-3 study found any difference in 30 day mortality rate (8.5% SK vs 8.9% tPA) and (10.6% for SK and 10.3% for tPA) respectively. In the GUSTO trial a more aggressive regimen was used, so called front-loaded tPA, producing a small but significant benefit favouring tPA (6.3% vs 7.3% p > 0.04). There were, however, an excess of strokes (0.72% for tPA vs 0.54% for SK). Combining deaths and strokes there was still a benefit favouring front-loaded tPA (6.9 % vs 7.8%).
Currently, in many countries streptokinase remains the first line treatment for AMI. This is because the advantage for tPA is modest and tPA is expensive ((£470) compared to SK (£80) per patient). Since streptokinase neutralising antibodies are formed from about day 4 onwards, tPA will need to be administered should the patient reinfarct after this time.
The lack of any large difference in clinical outcome between tPA and SK despite the difference in early angiographic patency needs to be explained. TPA is locally effective, with little systemic thrombolytic effect (for example on circulating plasminogen). It is, however, very specific, which is the cause for the excess in strokes. It has a short half life compared to SK. It has been clearly shown in animal models of arterial thrombotic occlusion that opening of the vessel by administration of tPA may be followed by early reocclusion, perhaps within minutes. The 90 minute angiogram cannot reflect the consequent reocclusion of the artery, which will happen less with SK which has a longer half life. Thus the increased patency with tPA may not translate into a decrease in mortality. The short half life of tPA means that heparin should be coadministered and continued for 24 hours although true benefit has never actually been proven.

What to give

Currently, the choice of thrombolytic varies by country and depends especially on the type of health care system and funding in place. In many countries, in the absence of previous administration the first line thrombolytic is SK (1.5 million units in 100 mls 5% dextrose/0.9% NaCl over 30-60 minutes). Alternatively, tPA is given as a 15mg bolus followed by 50mg over 60 minutes, then 35mg over a further 30 minutes. Based on the GUSTO study a case can be made for tPA in those presenting very early (<4 hours with large anterior infarcts). New plasminogen activators such as recombinant plasminogen activator (r- PA) and prourokinase are currently the subject of a number of clinical studies. Reteplase (rPA), is a nonglycosylated deletion mutant of wild type tPA. It is the first member of the third generation thrombolytics, has a longer half life and is given as a double bolus (10IU + 10IU). Equivalence trials comparing tPA and reteplase have demonstrated no difference in outcome and currently these two drugs are interchangeable, with decisions about use being based on availability and price. Lanoteplase has been withdrawn prior to launch because of patent issues and TNK-tPA is being trialled against tPA (ASSENT 2). Bleeding with this new agent was between 2.8% and 7.4% dependent on dose (ASSENT 1). Data suggest that there may be a role for "rescue" angioplasty in patients who fail to show electrocardiographic evidence of reperfusion. However, results of randomised trials addressing this issue are awaited.

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What new approaches are there to prevent restenosis following PTCA?

What new approaches are there to prevent restenosis following PTCA?

Percutaneous transluminal coronary angioplasty (PTCA) is a well-established treatment for patients with coronary artery disease. However, the excellent initial procedural outcome is limited by the late development of restenosis occurring in approximately 30% of cases between 3 and 6 months. The introduction of intracoronary stents, which now account for more than 70% of all interventional procedures has had only a modest effect on restenosis rates. There were over 20,000 angioplasty or related procedures in the UK in 1996 and it is easy to appreciate the clinical and economic burden of restenosis.

Pharmacological approaches

To date no pharmacological agent has had a significant effect on reducing the incidence of restenosis. There are a number of reasons for this including the lack of correlation between animal models and the situation in man, the drug doses used or the power of some of the trials. Recent interest has focused on the use of antiproliferative agents such as paclitaxel and tranilast.
The antioxidant Probucol has been shown to be effective in limiting restenosis after balloon angioplasty. However, lack of licensing in some countries, limited data on the clinical impact of treatment, and the fact that pre-treatment for 4 weeks is required, may all be factors in limiting its use.
Gene therapy involves the transfer of DNA into host cells with the aim of inducing specific biological effects. Vectors for gene delivery include plasmid DNA-liposome complexes and viral vectors such as the replication deficient recombinant adenovirus. Design of appropriate delivery devices has taken a number of directions including double balloon catheters and perforated balloons allowing high pressure injection through radial pores. Various approaches have been used to limit experimental restenosis by inducing cell death (e.g. fas ligand gene to induce apoptosis), inhibiting smooth muscle cell migration (e.g. overexpression of TIMP-1 and eNOS) or by inhibiting cell cycle regulators of smooth muscle cell proliferation (e.g. antisense c-myc or c-myb oligonucleotides). There is a vast amount of experimental data, with early results from gene therapy trials for angiogenesis, but clinical trials for restenosis are awaited.

Brachytherapy

Over the last few years there has been considerable interest in intravascular brachytherapy (radiation therapy). The ability of ionising radiation to halt cell growth by damaging the DNA of dividing cells, and the view that neointimal hyperplasia represented a benign proliferative condition led to its application in vascular disease. A variety of catheter based delivery systems and radioactive stents are available using either beta (e.g. 32P) or gamma (e.g. 192Ir) sources. A number of studies have shown impressive results on reducing restenosis rates and many more are underway but enthusiasm for the technique should be tempered because there are concerns about long term safety. Indeed there are very recent reports of unexpected late thrombotic occlusion.
Photodynamic therapy (PTD) involves the local activation of a systemically administered photosensitising agent by nonionising radiation in the form of non-thermal laser light. Many of the sensitising agents that have been studied have been products of porphyrin metabolism such as 5-aminolaevulinic acid. Much of the work in this field to date has been in the treatment of cancer but there is an accumulation of small and large animal data showing a reduction in neointimal hyperplasia after balloon injury. Favourable vessel wall remodelling has also been observed in a pig model of balloon coronary and iliac angioplasty. Reports of the clinical application of photodynamic therapy are limited but a clinical pilot study of adjuvant PDT in superficial femoral angioplasty showed it to be a safe and effective technique. Further work needs to be done to establish its role in coronary disease.

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Under what circumstances should the patient with unstable angina undergo PTCA or CABG?

Under what circumstances should the patient with unstable angina undergo PTCA or CABG?

Until recently, published trials and registry data comparing early invasive and conservative strategies in patients with unstable angina (UA) and non-Q wave myocardial infarction (NQMI) suggested no overall benefit from an early invasive approach. Indeed, there was the impression that patients fared better with an initial conservative approach. However, the most recently published trial (FRISC II),1 reflecting modern interventional practice, new stent technology and adjunctive medical therapies (e.g. the glycoprotein IIb/IIIa antagonists) together with improved bypass and myocardial preservation techniques and greater use of arterial conduits has shown significant mortality and morbidity benefit from an early invasive approach.
The first trial to assess these two management strategies, TIMI IIIB, randomised patients with UA/NQMI to angiography within 24-48 hours followed by PTCA/CABG if appropriate.2 The primary end point of death/MI/positive treadmill test at 6 weeks was 18.1% for the conservative strategy and 16.2% for the invasive strategy (p = NS). Death/MI occurred in 7.8% and 7.2% at 6 weeks (p = NS) and in 12.2% and 10.8% at 1 year (p = NS). However, 64% of patients crossed over to the invasive strategy because of recurrent angina or an abnormal treadmill test, raising doubts about the clinical application of the trial results.
The VANQWISH study similarly randomised patients with NQMI.3 Death or non-fatal MI occurred in 7% (invasive) vs 3.2% (conservative, p = 0.004) at hospital discharge, in 10.3% vs 5.7% at 1 month (p = 0.0012) and in 24% vs 18.6% at 1 year (p = 0.05). However, with longer follow up (23 months) the mortality difference was lost. Of note, 9% of eligible patients were excluded due to very high-risk ischaemic complications. In contrast to TIMI IIIB, only 29% patients crossed over from the conservative arm.
The OASIS registry highlighted different management strategies for UA by country.4 Angiography rates varied from 2% (Poland) to 58% (US) and 60% (Brazil) at 7 days. Rates of PTCA and CABG by 7 days were highest in the US and Brazil (15.9% and 11.7%) and lowest in Canada/Australia/Hungary/Poland (5% and 1.6%). However, MI and death rates were similar for all countries during a 6 month follow up. Countries with high intervention rates had higher stroke rates but lower rates of recurrent angina and readmission for unstable angina.
The FRISC II study,1 comparing early invasive and conservative strategies, together with the effect of placebo-controlled long term low molecular weight heparin (dalteparin), showed a reduction in death and myocardial infarction in the invasive group (9.4% vs 12.1% in the non-invasive group at 6 months, p = 0.031). Symptoms of angina and readmission were also halved by the invasive strategy. The greatest benefit was seen in high risk patients, in whom potentially beneficial treatments are often denied in routine clinical practice. By 6 months, 37% of the non-invasive group had crossed over to the invasive strategy. Although there was a higher event rate initially in the invasive group, associated with revascularisation, the event rate subsequently fell and the hazard curves crossed after 4 weeks. Thereafter, the event rate was consistently lower in the invasive group. Invasive treatment provided the greatest advantages in older patients, men, patients with a longer duration of angina, chest pain at rest and ST segment depression.
The favourable results of FRISC II reflect not only modern revascularisation technologies but probably also the intended delay prior to angiography and intervention. Patients in the invasive arm were initially stabilised medically, with the aim to perform all invasive procedures within seven days.
The consensus of opinion has thus changed and, where facilities permit, intensive medical therapy followed by angiography with a view to revascularisation is the preferred option for patients with unstable coronary artery disease.

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Medical treatments of unstable Angina treatments

What medical treatments of unstable angina are of proven benefit?

The treatment of unstable angina is dictated by the underlying pathophysiology, namely, rupturing of an atheromatous plaque and secondary platelet aggregation, vasoconstriction and thrombus formation.
Anti-ischaemic therapy
Nitrates relieve ischaemic pain but there is no evidence of prognostic benefit from their use.
Calcium antagonists are effective anti-ischaemic and vasodilator drugs. However, in the absence of beta blockade, nifedipine should be avoided due to reflex tachycardia. Verapamil and diltiazem have useful rate-lowering properties, but should be used cautiously in patients with ventricular dysfunction and patients already taking beta blockers.
Beta-adrenoceptor blockers are an important treatment in unstable angina, not only relieving symptoms but also reducing the likelihood of progression to infarction and cardiac death. There is no evidence to favour one class of beta blocker over another.
Antithrombotic therapy
Aspirin has an important and undisputed role in the treatment of unstable angina, reducing the risk of fatal/non-fatal MI by 70% acutely, by 60% at 3 months and by 52% at 2 years.1 A first dose of 160-325mg should be followed by a maintenance dose of 75mg daily.
Ticlopidine and clopidogrel, antagonists of ADP-mediated platelet aggregation, are possible alternatives in patients unable to take aspirin, although ticlopidine has important side effects and trials using clopidogrel have yet to be completed (e.g. CURE study).
Glycoprotein IIb/IIIa inhibitors (e.g. abciximab, tirofiban and eptifibatide) are potent anti-platelet agents and are effective, but costly, in patients with unstable angina undergoing PTCA. More recent data support a wider role for their use in the medical management of high-risk patients with unstable angina i.e. recurrent ischaemia, raised troponia levels, haemodynamic instability, major arrhythmia and early post-infarction unstable angina.
Unfractionated heparin reduces ischaemic episodes but most trials have not shown greater benefit from heparin and aspirin compared with aspirin alone. However, a meta-analysis gave a 7.9% incidence of death/MI with the combination compared with 10.4% with aspirin alone.
Low molecular weight heparins (e.g. dalteparin, enoxaparin) are at least as effective as heparin and are tending to replace heparin as standard therapy.
Thrombolytics are of no proven benefit and should be avoided.

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What are the risks of myocardial infarction?

What are the risks of myocardial infarction and death in someone with unstable angina during hospital admission, at six months and one year?

The risks of myocardial infarction (MI) and death following the diagnosis of unstable angina (UA) depend on the accuracy of the diagnosis. Braunwald’s classification categorises patients according to the severity of the pain (new onset/accelerated and pain at rest, either within the last 48 hours or >48 hours) and to the clinical circumstances (primary, secondary (e.g. to anaemia) and post-infarction). Using this classification, one study showed an in-hospital AMI/death rate of 11% for patients with rest pain within the last 48 hours, 4% for patients with rest pain >48 hours previously and 4% for patients with new onset/accelerated angina. The in-hospital AMI/death rate was markedly raised in patients with post-infarct angina (46%) compared with patients with "primary" unstable angina.
The event rate is highest at and shortly following presentation, falling off rapidly in the first few months to a level similar to stable angina patients after one year. Patients with new onset angina have a better prognosis than those with acceleration of previously stable angina or patients with rest pain. Patients with accelerated or crescendo angina have an in-hospital mortality of 2-8% and a 1 year survival of 90%. Although patients with non- Q wave MI, also considered within the umbrella term UA, have a more benign in-hospital course than Q-wave MI patients, they have higher readmission, reinfarction and revascularisation rates subsequently. Infarct extension in-hospital is associated with a far worse prognosis in non-Q wave MI (43% mortality, vs 15% in Q wave MI). The following are also associated with a worse prognosis in unstable angina: ST segment deviation on the ECG (but not T wave changes), elevated cardiac enzymes, transient myocardial ischaemia on Holter monitoring, an abnormal predischarge exercise test, extensive coronary artery disease and impaired left ventricular function.
The OASIS registry, gave 7 day death/MI rates of 3.7-5.6% and 6 month rates of 8.8-11.9%. Similarly, the VANQWISH trial gave the following rates of death/non-fatal MI: 3.2-7% at hospital discharge, 5.7-10.3% at 1 month and 18.6-24% at 1 year.

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What is the role of troponin T in the diagnosis and risk stratification of acute coronary syndromes?

What is the role of troponin T in the diagnosis and risk stratification of acute coronary syndromes?

A significant proportion of patients presenting to accident and emergency departments complain of chest pain. Early risk stratification is vital with the primary aim being to identify lifethreatening conditions such as acute coronary syndromes (ACS) and ensure their appropriate management, especially since the majority of patients have either non-cardiac chest pain or stable angina and are at low risk.

Standard diagnostic approach

The standard approach to the diagnosis of acute chest pain is to combine features of the clinical history, including cardiac risk factor profile, with electrocardiogaphic features and biochemical markers. The Braunwald classification was initially introduced to allow the identification of patients with unstable angina at different levels of risk. It correlates well with in-hospital event rate and prognosis. Unfortunately symptoms may be difficult to interpret and clinical assessment alone is insufficient for risk stratification. Many studies have shown that admission 12-lead ECG provides direct prognostic information in patients with ACS. However, as many as 50% of patients ultimately diagnosed as having either unstable angina or myocardial infarction present with either a normal ECG or with minor or non-specific ECG changes only.
Traditionally the biochemical diagnosis of myocardial injury was confirmed by measurements of non-specific enzymes such as CK-MB mass or myoglobin, whose levels may also be elevated after non-cardiac injury. The availability of rapid and accurate bedside assays of cardiac troponin T has transformed the diagnostic process. Troponin T is an essential structural protein of the myocardial sarcomere. It is a highly sensitive and specific marker of myocardial damage that is not detectable in the healthy state. Troponin T is released within 4-6 hours of injury peaking after 12 to 24 hours. Elevated levels of troponin T reflect even minor myocardial damage and remain detectable for up to 14 days. An elevated troponin T has a predictive value for myocardial ischaemia several times higher than CK-MB mass.

Troponin T as a diagnostic tool

Troponin T can be used both as a diagnostic and a prognostic tool in the Accident and Emergency Department. Repeated troponin assays taken 4-6 hours apart have been used to successfully identify all patients with MI even in the absence of ST elevation.1Individuals who were troponin T negative were shown to be at low short term risk. Troponin T accurately reflects the degree of myocardial necrosis with the overall risk of death following an ACS being directly related to the levels detected. Data from the Fragmin During Instability in Coronary Artery Disease trial (FRISC) demonstrated that patients with the highest levels of troponin T following an ACS carried the highest risk of death and MI, in contrast to those who were troponin T negative who were at low risk.2 A subset from the GUSTO IIa trial had similar findings for non-ST elevation ACS where troponin T positive patients had a much higher risk of death and heart failure than troponin T negative individuals.

Risk stratification

The initial step in risk stratification is an ECG. Patients with acute ST elevation are considered to have an acute MI and require reperfusion therapy according to local protocols. Individuals with ST depression are also at high risk and require admission for further evaluation. The presence of a positive troponin T in this group further confirms them as high risk. In situations where patients present either with a normal ECG or with T wave changes only, the value of a positive troponin T is vital in risk stratification. All patients who are troponin T positive should be considered as high risk, whilst in contrast, a negative troponin T 12 hours or more after the onset of symptoms puts the individual in a low risk group. If the result of a negative troponin T test taken 12 hours or more after the onset of chest pain is taken in conjunction with a pre-discharge exercise test, this further reduces the chance of an inappropriate discharge. Figure 20.1 illustrates one possible management algorithm.



Conclusion

Troponin T has a vital role in the triage of patients presenting with chest pain. A positive test identifies high-risk individuals who may benefit from aggressive anti-platelet therapy or early intervention, whilst negative troponin T tests 12 or more hours after the onset of symptoms identify those at low risk who can be considered for early hospital discharge.

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Which class of antianginal agent should I prescribe in stable angina? Does it matter?

Which class of antianginal agent should I prescribe in stable angina? Does it matter?

Nitrates
All patients with angina pectoris should have sublingual glyceryl trinitrate (GTN) for the rapid relief of acute pain. Long-acting isosorbide dinitrate (ISDN) and isosorbide mononitrate (ISMN) preparations are also available but have not been shown to influence mortality in post-myocardial infarction (MI) patients.
Beta blockers
In the absence of contraindications, beta blockers are preferred as initial therapy for angina. Evidence for this is strongest for patients with prior MI. Long term trials show that there is a 23% reduction in the odds of death among MI survivors randomised to beta blockers.
Calcium antagonists
Calcium antagonists (especially those which reduce heart rate) are suitable as initial therapy when beta blockers are contraindicated or poorly tolerated. Outcome trials are underway but there is currently little evidence to suggest they improve prognosis post-MI, although diltiazem and verapamil may reduce the risk of reinfarction in patients without heart failure, and amlodipine may benefit certain patients with heart failure.
Other agents
Nicorandil, a potassium channel opener with a nitrate moiety, and the metabolic agent, trimetazidine, may also be useful, but these have not been tested in outcome studies. Many patients with exertional symptoms may need a combination of anti-anginals, but there is little evidence to support the use of "triple therapy". Patients requiring this should be assessed for revascularisation. There are no important differences in the effectiveness of the principal classes of anti-anginal used singly or in combination. Choices should be based on those producing fewest side effects, good compliance and cost effectiveness.

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What are hibernating and stunned myocardium? What echocardiographic techniques are useful for detecting them? How do these methods compare with others

What are hibernating and stunned myocardium? What echocardiographic techniques are useful for detecting them? How do these methods compare with others available?

The physiologic abnormalities that are associated with resting myocardial dysfunction and viable myocardium range from reduced resting myocardial flow and preserved metabolic uptake of 18F-2-Deoxyglucose (FDG) (hibernating myocardium) to patients in whom resting myocardial flow is preserved (stunned myocardium). Animal studies1 suggest that stunning may progress to hibernation as part of an adaptive response. As coronary flow reserve decreases, fasting FDG uptake increases while resting flow remains normal (chronic stunning). Later on, during continuing ischaemia, flow is reduced while FDG uptake continues, characteristic of hibernation.
Assessing myocardial viability is important in coronary artery disease patients with ventricular dysfunction because its presence improves left ventricular function and survival following revascularisation. Diagnostic methods include positron emission tomography (PET), based on the detection of metabolic activity, Tl single-photon emission computed tomography (Tl-SPECT), to assess cell membrane integrity by rest/redistribution and the assessment of contractile reserve by dobutamine stress echocardiography. Echocardiography can assess the presence of myocardial viability by looking at contractile reserve following inotropic stimulation with dobutamine (dobutamine stress echocardiography). This differentiates viable myocardium (presence of contractile reserve) from non-viable scarred myocardium (absence of contractile reserve) in patients with ventricular dysfunction at rest. More recently, myocardial contrast echocardiography (MCE) has been proposed as a method to assess myocardial perfusion and viability. Myocardial opacification produced by the presence of microbubbles in the coronary microcirculation has been considered synonymous with preserved microvascular integrity.
Using detailed histology from explanted hearts in patients undergoing heart transplantation, Baumgartner et al. compared PET, SPECT and echo to detect viable myocardium. While segments with >50% of viable myocytes were equally well predicted by all three non-invasive tests, in segments with <50% of viable myocytes the response to dobutamine was poor in relation to SPECT and PET, which showed equal sensitivities. However, taking survival as an end point, patients with at least 42% of viable segments during dobutamine stress echocardiography had a better long term survival following revascularisation.

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Who should have a thallium scan?

Who should have a thallium scan? How does it compare with standard exercise tests in determining risk ?

Exercise electrocardiography (ECG) is often the initial test in patients with chest pain being investigated for coronary artery disease (CAD). When this is unhelpful or leaves doubt then myocardial perfusion imaging (MPI) is recommended. This may occur when equivocal ST segment changes occur with exercise, the exercise ECG is abnormal in a patient at low risk for CAD or normal in a patient at high risk. MPI should be used instead of exercise ECG when a patient has restricted exercise tolerance and when the resting ECG is abnormal. Importantly, recent data confirm that investigative strategies for chest pain which include MPI are cost effective.
The prognostic value of MPI arises from the relationship between the depth and extent of perfusion abnormalities and the likelihood of future cardiac events. A normal MPI scan after adequate stress predicts a favourable prognosis (cardiac event rate below 1% annually). Conversely, severe and extensive inducible perfusion defects imply a poor prognosis, as do stress-induced left ventricular dilatation and increased lung uptake of tracer. Several studies have shown that MPI is the most powerful single prognostic test and that it provides independent and incremental information to the exercise ECG in nearly all settings., A prognostic strategy including MPI is also cost effective.

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Stratification data for risk from exercise tests in patients with angina

What are the stratification data for risk from exercise tests in patients with angina? Which patterns of response warrant referral for angiography?

The best evidence available on these questions is found in the two studies that used the appropriate statistical techniques to find the risk markers that were independently and statistically associated with the time to cardiovascular events. Both studies were performed in large populations (>3000 patients with probable coronary disease) and had five year follow-up. The Veteran’s Affairs (VA) study was performed only in men and the risk factors identified were a history of congestive heart failure (CHF) or digoxin administration, an abnormal systolic blood pressure (SBP) response, limitation in exercise capacity, and ST depression. The DUKE study included both genders and has been reproduced in the VA as well as other populations. It includes exercise capacity, ST depression and whether or not angina occurred. The DUKE score has been included in all of the major guidelines in the form of a nomogram that calculates the estimated annual mortality due to cardiovascular events.
In general, an estimate more than 1 or 2% is high risk and should lead to a cardiac catheterisation that provides the "road map" for intervention. Certainly a clinical history consistent with congestive heart failure raises the annual mortality of any patient with angina and this is not considered in the DUKE score. Exercise capacity has been a consistent predictor of prognosis and disease severity. This is best measured in METs (multiples of basal oxygen consumption). In clinical practice this has been estimated from treadmill speed and grade but future studies may show the actual analysis of expired gases to be more accurate. Numerous studies have attempted to use equations to predict severe angiographic disease rather than prognosis but these have not been as well validated.

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What are the risks of exercise testing? What are the contraindications?

What are the risks of exercise testing? What are the contraindications?

Although exercise testing is generally considered a safe procedure, acute myocardial infarction and death have been reported (up to 10 per 10,000 tests performed in some studies). The risk is greater in the post-MI patient and in those being evaluated for malignant ventricular arrhythmias. The rate of sudden cardiac death during exercise has ranged from zero to as high as 5% per 100,000 tests performed. Guidelines for exercise testing for North America have now been made available.1 Table 15.1 lists absolute and relative contraindications to exercise testing. In patients recovering from acute myocardial infarction, a low level exercise test before discharge helps identify those patients at high risk for future cardiac events. In addition to being a source of reassurance to the patient and his/her family, the test may also provide guidelines for an exercise programme and resumption of work and normal sexual activities.
The sensitivity ranges from a low of 40% for single vessel coronary artery disease to up to 90% for angiographically severe three vessel disease, with a mean sensitivity of 66%. The specificity of the test is ~85% when at least 0.1mV horizontal or downsloping ST-segment depression are used as markers of ischaemia. In patients with a positive exercise test, an ischaemic threshold less than 70% of the patient’s age predicted maximum heart rate is indicative of severe disease.
Various drugs may affect interpretation of the exercise test either because of haemodynamic alterations in the myocardial response to exercise or because the drug has direct electrophysiologic effects that can affect the interpretation of the electrocardiogram. The decision to stop medications prior to an exercise test depends on the drug and the reasons for using it. Some institutions withhold beta blockers for 48 hours prior to exercise testing if there is doubt about the diagnosis of coronary artery disease.

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What is the sensitivity, specificity and positive predictive value of an abnormal exercise test?

What is the sensitivity, specificity and positive predictive value of an abnormal exercise test?

While sensitivity (% of those with disease who have an abnormal test) and specificity (% of those without disease who have a normal test) are relatively independent of disease prevalence they are reciprocally related and dependent upon the cut point or criterion chosen for diagnosis. The positive predictive value of an abnormal test (% of those with an abnormal test that have disease) is directly related to the prevalence of disease. Another way to compare the diagnostic characteristics of a test is by use of predictive accuracy that is the percentage of total true calls (both negative and positive). While it is affected by disease prevalence, since diagnostic testing is usually only indicated when the pretest probability is 50% (i.e. a disease prevalence of 50%) this measurement is a simple way of comparing test performance.
Meta-analysis of the exercise test studies with angiographic correlates has demonstrated the standard ST response (1mm depression) to have an average sensitivity of 68% and a specificity of 72% and a predictive accuracy of 69%. But most of these studies have been affected by work up bias that means that those with abnormal tests were more likely to be entered into the studies to be catheterised. When work up bias is removed by having all patients with chest pain undergo catheterisation different results are obtained though the predictive accuracy remains the same. In such a study we found a sensitivity of 45% and a specificity of 85%. It appears that this is how the test performs in the clinic or doctor’s office. However, the inclusion of clinical and other test results in scores can increase the predictive accuracy of the standard exercise test to nearly 90%.

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Is there a role for prescribing antioxidant vitamins to patients with coronary artery disease?

Is there a role for prescribing antioxidant vitamins to patients with coronary artery disease? If so, who should get them, and at what dose?

Three large prospective studies have shown that vitamin E users have a 40% lower rate of coronary artery disease. At least 100 IU/day of supplement is required to gain benefit. However, one large study in postmenopausal women showed no benefit from vitamin E supplementation, but high dietary vitamin E consumption reduced the risk by 58%.
At present there are only two intervention studies in patients with coronary artery disease available to guide therapeutic decisions. The CHAOS study1 used 400 or 800 IU/day while the ATBC study2 used 50 IU/day. Both studies showed that vitamin E does not save lives in patients with coronary artery disease and that it may increase the number of deaths. Both studies also agree that non-fatal myocardial infarctions are reduced significantly, by 38% in the ATBC study and by 77% in the CHAOS study, with a 53% reduction in combined events in the latter study. In the CHAOS study of 2002 patients, 27 heart attacks were prevented at the expense of 9 additional deaths (albeit statistically non-significant) while in the ATBC study the 15 fewer non-fatal heart attacks were balanced by 15 additional cardiovascular deaths. In the latter study it could be argued that the low dose of vitamin E used did not prevent myocardial infarction but when one occurred it was more often fatal. Until more compelling evidence is available the potential adverse effect of vitamin E does not outweigh the benefit of fewer non-fatal myocardial infarctions. Patients should be advised to eat diets rich in fruit and vegetables instead.

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