coronary care manual 2e by thompson

Coronary Care ManuaL

Peter Thompson

2e

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31 • Beta-blockers

Coronary Care Manual 2ePeter Thompson MD FRACP FACC MBA

ContributorsJoe Alpert, Con Aroney, Phillip EG Aylward, Gust Bardy, Phil Barter, George Beller, Rinaldo Bellomo, Tandeep Bhatti, Stefan Blankenberg, David Blythe, Pamela Bradshaw, David Brieger, Tom G Briffa, Terence J Campbell, Matt Cavender, Derek Chew, Sharon Chih, Philip Cooke, Samir Damani, Tim Davis, Rajinder Dhamija, Geoffrey Donnan, Hooi Ee, Nabil El Sherif, Maros Elsik, Judith Finn, Peter Fletcher, Keith Fox, Valentin Fuster, Alex Gallus, Ilan Goldenberg, Jonathan Golledge, Lance Gould, Cindy Grines, David Hare, Michel Haissaguerre, Ian Hamilton Craig, Harvey Hecht, Siobhan Hickling, David Hillman, Kwok M Ho, John D Horowitz, Joe Hung, Luan Huynh, Ian Jacobs, Allan Jaffe, Konrad D Jamrozik, Michael Jelinek, Nils

Johnson, Desmond Julian, David Kaye, Till Keller, Anne Keogh, Leonard Kritharides, Henry Krum, Ashok Kumar, Paul E Langton, Mark Lennon, Harry Lowe, Peter MacDonald, Micha Maeder, Andrew Maiorana, Tom Marwick, Jane McCrohon, Harry G Mond, Dr Moreno, Arthur Moss, David Mountain, David Muller, Mark Newman, S Mark Nidorf, Magnus Ohmann, Bertram Pitt, Brad Power, Abhiram Prasad, David Richards, James S Robinson, David Ross, Javier Sanz, Karin Schenck-Gustafsson, Marion Simpson, Peter Sinnaeve, Graeme Sloman, Paul Stein, Paul Stobie, Peter Stone, Rajesh Subbiah, David Taggart, Angus Thompson, Kristian Thygesen, Mark Toogood, Eric Topol, Luke Torre, Harvey White, Alex Wilson, Rukshen Weerasooriya, Frans Van der Werf, Ian Yusoff

The Coronary Care Manual 2e is designed as a practical manual for management of the acute coronary patient. Achieving a balance between the large and rapidly changing evidence base and practical application in the CCU, ICU, ED and ambulance is a key aim of the book. The contributing authors are carefully chosen because of their authoritative understanding of the evidence.

The book covers recent advances as well as basic subjects over a broad range of coronary care medicine and it provides specifi c advice on the management of many common clinical problems with enough detail to eliminate the need to refer to a larger reference book - an ideal companion for a night ‘on call’.

Foreword by Robert Califf

SECTION HEAD

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Coronary Care Manual 2ePeter Thompson

Sydney Edinburgh London New York Philadelphia St Louis Toronto

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CONTENTS

Section 1 Background to coronary care 1 History and future of the coronary (cardiac)

care unit 2 Design and management of the coronary care unit 3 Applying evidence-based medicine in the coronary

care unit 4 Redefi nition of acute coronary syndromes and

universal myocardial infarction

Section 2 Epidemiology, genetics and risk factors 5 Clinical epidemiology of acute myocardial infarction

and coronary heart disease 6 Molecular genetics of atherosclerosis and acute

coronary syndromes

Section 3 Pathophysiology 7 Coronary risk factors 8 Pathophysiology of atherosclerosis 9 Pathophysiology of coronary thrombosis10 Pathophysiology of myocardial infarction11 Pathophysiology of ventricular arrhythmias in

myocardial infarction and sudden cardiac death12 Pathophysiology of cardiac failure

Section 4 Evaluations of the patient13 History14 Physical examination15 Electrocardiography16 Biochemical markers of myocardial necrosis17 Novel biomarkers in evaluation of acute coronary

syndrome18 Chest x-ray19 Echocardiography20 Exercise testing21 Radionuclide imaging 22 Coronary computed tomographic angiography in

the emergency department23 Role of positron emission tomography24 Cardiac magnetic resonance imaging25 Coronary angiography26 Electrocardiographic monitoring27 Hemodynamic monitoring

Section 5 Drug therapies28 Oxygen therapy29 Analgesia30 Antiarrhythmic drugs31 Beta-blockers

32 ACE-inhibitors and angiotensin receptor blockers33 Aldosterone blockade: role in the coronary care unit34 Calcium channel blockers35 Nitrate therapy in the coronary care unit36 Alternative antianginal agents for acute coronary

syndromes37 Diuretics, digoxin, and electrolytes38 Inotropic and vasoactive agents39 Fibrinolytic therapy40 Intravenous heparin, low-molecular-weight heparins,

and thrombin antagonists41 Intravenous antiplatelet agents42 Oral antiplatelet therapy43 Oral anticoagulants: vitamin K antagonists, factor

Xa inhibitors, and thrombin-inhibitors44 Lipid management after a coronary event 45 Stabilizing unstable plaque in acute coronary

syndromes

Section 6 Non-drug therapies46 Vascular access and ultrasound guidance techniques47 Basic life support48 Advanced life support49 Positive airway pressure therapies50 Circulatory assist devices including the intraaortic

balloon pump51 Cardiac transplantation selection criteria52 Stem cells in myocardial injury53 Cardioversion and defi brillation54 Cardiac pacemakers and cardiac resynchronization

therapy 55 Catheter ablation of arrhythmias56 Implantable cardioverter defi brillators in patients

with coronary artery disease57 Pacemaker insertion and implantable cardioverter

defi brillator insertion58 Percutaneous coronary intervention59 Coronary artery bypass surgery

Section 7 Acute coronary problems 60 Prehospital coronary care61 Acute myocardial infarction: emergency department

care62 Acute myocardial infarction: coronary care unit

admission and care63 Management of ST-elevation myocardial infarction64 Management of non-ST-elevation acute coronary

syndromes

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65 Acute myocardial infarction: management of cardiac arrhythmias and conduction disturbances

66 Acute myocardial infarction: cardiac failure and pulmonary edema

67 Cardiogenic shock68 Acute myocardial infarction: other complications69 Acute myocardial infarction: right ventricular

infarction70 Apical ballooning syndrome (tako-tsubo or

stress-induced cardiomyopathy)71 Other causes of chest pain

Section 8 Other cardiac problems72 Atrial fi brillation73 Ventricular tachycardia74 Other cardiac arrhythmias 75 The cardiac surgery patient76 The cardiac catheterization patient 77 Care of the percutaneous coronary intervention

patient78 The pre- and postoperative management

of the cardiac transplant recipient79 Hypertensive crises80 Aortic dissection81 Pericardial effusion and tamponade82 Pulmonary embolism in the coronary care unit

Section 9 Special problems in the coronary care unit patient83 Management of diabetes in the coronary care unit84 Renal dysfunction in the coronary care unit85 Gastroenterology emergencies in the coronary care

unit86 Stroke in the coronary care unit87 Bleeding complications and transfusion in acute

coronary syndrome88 Depression and coronary heart disease89 Gender issues in the coronary care unit

Section 10 Postcoronary management90 Management of the postcoronary patient91 Secondary prevention of coronary heart disease92 Postcoronary diet therapy93 Postcoronary rehabilitation, heart failure,

and exercise

Appendix 1 IV doses for single-use drugs

Appendix 2 Loading and maintenance dosage for infusion

Appendix 3 Useful cardiology websites

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16 • Biochemical markers of myocardial necrosis

16 Biochemical markers of myocardial necrosis

Allan S. Jaffe

For many years, assays of cardiac biomarkers have been used to aid in the detection of incident myocardial infarction (MI), and detection of reinfarction. 1 Bio-markers used for this purpose have been total creatine kinase (CK), CK isoenzymes (CK-MB), aspartate ami-notransferase (AST), and lactic dehydrogenase (LD). Seventeen years ago now, a more cardiac specifi c bio-chemical, troponin (cTn), was introduced; 2 this for most, if not all, clinical purposes has now supplanted all of the others. 3 The time course of biomarker release and disappearance is shown graphically in Figure 16.1 .

CREATINE KINASE, ISOENZYMES AND ISOFORMS The use of creatine kinase as a biomarker of acute myo-cardial infarction (AMI) was fi rst described in 1960. 4 When assays for the more specifi c CK-MB isoenzyme were developed, it became the standard. 5 At present, it has itself been supplanted by troponin, and its use diagnostically is questionable at best and should be confi ned to those unusual situations in the developed world where for some reason troponin measurements are not available. 3

Skeletal muscle contains mostly the CKMM iso-enzyme and contains between 3% and 7% CK-MB. Cardiac muscle contains 15 – 30% CK-MB. 2 Follow-ing irreversible ischemic necrosis of myocardial cells,

there is a leakage of creatine kinase from the intracel-lular to the extracellular compartment. The enzyme in the interstitial space then passes into the lymphatic system before reaching the circulation. 4 During pas-sage through the lymphatics, there is a process of oxi-dation, which breaks down the enzyme so that only roughly 15% of the CK released from the heart ap-pears in the circulation. 6 In the absence of reperfusion and because there are moderate constitutive levels of CK-MB in blood, it takes at least 3 – 4 hours for enough enzyme to appear in the blood to be clearly recognized. 2 The enzyme is widely distributed and is cleared by the reticulo-endothelial system. 7 The inter-play between the rate of release, distribution volume, and rate of degradation explains the typical plasma curves of CK with appearance in the plasma at 3 – 4 hours postinfarction, rising to a peak at 20 – 24 hours and gradually returning to normal over the subse-quent 3 – 4 days. CK-MB follows similar kinetics with a slightly earlier rise and earlier peak and slightly more rapid clearance. 5

When coronary reperfusion occurs before myocar-dial necrosis has been complete, there is a “shift to the left” of the curve with an early peaking and more rapid clearance. In addition, the percentage of CK-MB that appears in the blood is increased due to the washout that bypasses lymphatic degradation. 8

Like CK, CK-MB lacks cardiac specifi city because the amount of CK-MB, though a modest percentage of 3 – 11% in skeletal muscle, is substantial in absolute terms. 9 The concept of the ratio of CK-MB to total CK 10 has been advocated to overcome this problem. However, this approach will be misleading when myo-cardial necrosis is present in conjunction with skeletal muscle damage, such as after surgery or trauma. 11 – 13 Conversely, in patients with chronic muscle diseases such as muscular dystrophy or polymyositis, there is re-expression of the B chain gene and an increase in the percentage of CK-MB in the muscle; this can lead to substantial release. 3 Usually this results in a pattern of persistent CK-MB elevations, rather than the typi-cal rise and fall seen with myocardial necrosis. Rarer causes of CK-MB elevation include renal failure or some tumors. As with total CK, hypothyroidism may cause persistently abnormal CK-MB because of de-layed clearance. 3

Myoglobin and CK isoforms

Troponin (large MI)

CKMB

Troponin (small MI)

10% CV/99th percentile

0 1 2 3 4

50

20

10

5

210

5 6 7 8 9

Days after onset of AMI

Mul

tip

les

of

the

upp

er li

mit

of

norm

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Figure 16.1 Time course of release of troponin, CK-MB and myoglobin. With present day assays, troponin rises faster than the others and stays elevated for a longer period of time. Reproduced from Shapiro BP, Jaffe AS. Cardiac biomark-ers. In: Murphy JG, Lloyd MA, eds. Mayo Clinic cardiology: concise textbook. 3rd edn. Rochester: Mayo Clinic Scientifi c Press and New York: Informa Healthcare USA; 2007:773 – 780.

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SECTION 4 • EVALUATIONS OF THE PATIENT

CK-MB values are much lower in women than in men, thus gender-specifi c reference values are essential. 14

Sensitivity and specifi city of CK-MB have been improved by the development of automated immuno-assays using monoclonal anti-CK-MB antibodies 15 – 17 , which are clearly the preferred assays for use.

Assays of isoforms of CK were proposed to im-prove early diagnosis 18,19 and were once advocated for use. 20, 21 However, this strategy is no longer needed if sensitive troponin assays and the cut-off values recom-mended in the guidelines are used. 3

LACTIC DEHYDROGENASE (LD) AND ASPARTATE AMINOTRANSFERASE (AST) These analytes were measured in the past but have no role in the modern day diagnosis of myocardial injury per the 2000 22 or 2007 23 guidelines.

MYOGLOBIN Myoglobin is a small molecule that is rapidly released from myocardium as a result of myocardial necrosis. It was touted as a possible early marker of myocardial infarction, 24 – 26 but it is no longer needed if high sensi-tivity troponin assays are used with the cut-off values advocated in the guidelines. 22,23

TROPONINS The troponin complex consists of three different pro-tein regulatory subunits: T, I, and C. Cardiac tropo-nin I and T are antigenically distinct from the skeletal muscle troponins, a property which confers a high degree of cardiac specifi city to elevations; 27,28 cTnI is not found outside of the heart. Fetal isoforms of cTnT can be found in skeletal muscle but are not detected by the antibodies now used in the cTnT assay. 27,28 There is only one assay for cTnT but a large number of cTnI. Thus, clinicians must know the assay used locally since the numbers from one assay bear little relation-ship to the values with other assays. There appear to be two distinct pools of cTn: an early releasable pool

and a structurally bound pool that is released as the area of damage is remodeled. The early releasable pool is responsible for the early rise in cTn, and the structural pool for its persistence for 10 – 14 days after events. 28

In general, point-of-care assays are far less sensi-tive than laboratory-based assays. 7 Thus, the former should be used only if the turn-around time for results is excessive (> 60 minutes) 22,23 and with recognition that some patients with elevated values in laboratory-based assays will not be found to have elevated values in point-of-care assays.

The sensitivity and specifi city of troponin I and T are substantially better than that of CK-MB for the diagnosis of myocardial infarction. 27,29 With contemporary assays, cTn using the 99th percentile of a reference population detects a substantial num-ber of additional patients over and above CK-MB. The percentage increment varies with the assays in-volved but can be as high as 186%. 29 It is now clear that these patients have a prognosis similar in regard to the time course of mortality and recurrent infarc-tion but with a slightly better short term prognosis than those with elevations of CK-MB. 30 – 32 These individuals have more severe coronary artery dis-ease than patients without elevations of cTn, lower TIMI fl ow grades, and more procoagulant activ-ity 33 – 35 ( Fig 16.2 ). Even with the fi rst iteration of assays, it was clear that troponin rose to abnormal levels earlier than did CK-MB (median 3.8 hours for troponin T versus 4.8 hours for CK-MB, 36 and this has been even greater with the newer, more sensi-tive assays. Furthermore, levels remain elevated for up to two weeks post-MI. With the initial assays, cTnI appeared to be more specifi c than troponin T, 11 which was thought to manifest false positive eleva-tions in some studies. 37 This has now been shown to be due to the use of a non-specifi c tag antibody that detected fetal forms of cardiac cTnT and skeletal muscle isoforms. 38,39 The assay was reconfi gured after the fi rst generation with new and more specifi c

P < 0.001

72.0

64.8

29.3 42.1

7.0

42.515.6

58.1

74

72

70

68

66

64

62

60

702020

40

30

20

10

0

15

10

5

0

60

50

40

30

20

10

0

P < 0.001P = 0.02

TnT (< 0.01) TnT (> 0.01)

P = 0.03

Ste

nosi

s (%

)

Thr

om

bus

(%)

TFG

0/1

(%)

TM

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Figure 16.2 Coronary anatomy in patients with ACS with and without elevated troponin measurements. Reproduced with permission from Sciricaa BM, Morrow DA. Troponins in acute coronary syndromes. Prog Cardiovasc Dis. 2004;47(3):177 – 188.

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antibodies that eliminated any suggestion of a lack of specifi city. 40 – 41

Diagnosis of myocardial infarction Serial quantitative levels of cTn are recommended for the diagnosis of AMI because of their greater sensi-tivity than other markers and their almost absolute specifi city for myocardial injury. 22,23 Measurements at zero time and at least 6 hours after the onset of symp-toms are recommended, but some would prefer to add a sample at 3 hours given recent data indicating that up to 80% of patients with AMI can be identifi ed by 3 hours after the onset of symptoms with contemporary sensitive troponin assays and use of the 99th percentile value as recommended by the guidelines. 42 Exclusion of AMI may take up to 6 hours with present assays, although there is the suggestion that the use of still more sensitive assays may reduce both the time to rule in and the time to rule out substantially. 43 Abnormal plasma levels peak at 18 – 24 hours in the absence of reperfusion (6 – 18 with reperfusion) and return to nor-mal after 10 – 14 days (see Fig 16.1 ). 27 However, it is now clear that elevations of cTn occur due to a variety of cardiac insults ( Box 16.1 ) and that some patients can have chronic elevations. 27 The fi rst group in which this was recognized comprised those with renal failure where elevations are frequent. 44 However, recent data suggest that patients with heart failure and/or LVH can also have such elevations. Up to 0.7% of an apparently stable population fi t this description. 45 If it is 0.7% in

the general population, it is likely higher in the emer-gency department and still higher in the hospital. Thus, as with patients with renal failure, in addition to a value greater than the 99th percentile, a dynamic pattern of values is essential. 46,47 Patients with acute events should have rising or, if late, falling patterns. Using this as a criterion will improve the specifi city of detec-tion for acute events and thus AMI. However, patients who present late, near the time when peak values are occurring, might not manifest a rising pattern or might not provide an adequate increment of values because the values are already so high. Thus, implementation of this criterion, as with all others, requires an element of clinical judgment.

If quantitative serial cTn values are not available, CK-MB mass measurements at the same intervals are a reasonable but not an ideal substitute. 23,24 AST levels and/or total LD or LD 1 :LD 2 ratios are no longer recom-mended. Myoglobin does not have a place in the rou-tine diagnosis of MI because of poor specifi city. 23, 24

Early detection of myocardial infarction Considerable effort has been expended in recent years on the development of rapid assay techniques of non-specifi c markers for the earliest possible detection of myocardial necrosis. Rapid assay techniques are now available for CK-MB, 15 CK-MB subforms, 21 myoglobin, 26 and fatty acid binding protein. 48 None of these markers can reliably exclude myocardial infarction at the time of admission to hospital. Fur-thermore, recent data show that the use of contem-porary cTn assays and the 99th percentile value of the reference range obviate the need for any of these approaches. 49 – 51

Estimation of cTn not only allows for the early de-tection of AMI but also is a potent determinant of sub-sequent mortality and recurrent events. 30 – 32,52

The role of these techniques in cardiac decision making in the emergency room is now clear. Individu-als with STEMI, which is a clinical diagnosis, require admission and early reperfusion therapy. Primary per-cutaneous coronary intervention (PCI) is preferred. 53 Biomarkers should not be used in this situation since time is of the essence. Patients with elevations in tro-ponin who do not have ST-segment elevation require and benefi t from aggressive anticoagulation, the use of platelet IIB/IIIA anti-platelet agents, and an early in-vasive strategy. 53 Those with ST-segment depression are the highest risk subset. However, those with only T wave abnormalities and/or normal ECGs still ben-efi t from treatment. At present, there are no compelling data that immediate invasive intervention is required absent hemodynamic instability but early (within 24 – 48 hour) intervention is advised compared to longer delay. 53 The primary issue to consider in many of these patients is whether there are alternative causes for the cTn elevations since this sensitive marker of cardiac

BOX 16.1 ELEVATIONS OF TROPONIN IN THE ABSENCE OF OVERT ACUTE ISCHEMIC HEART DISEASE

• Cardiac contusion, or other trauma including surgery, ablation, pacing, etc

• Congestive heart failure—acute and chronic • Aortic dissection • Aortic valve disease • Hypertrophic cardiomyopathy • Tachy- or bradyarrythmias, or heart block • Apical ballooning syndrome • Rhabdomyolysis with cardiac injury • Pulmonary embolism, severe pulmonary hypertension • Renal failure • Acute neurological disease • Infi ltrative diseases, eg amyloidosis, hemochromatosis,

sarcoidosis, and sclerodema • Infl ammatory diseases, e.g. myocarditis or myocardial

extension of endo-/pericarditis • Drug toxicity or toxins • Critically ill patients, especially with respiratory failure,

or sepsis • Burns, especially if affecting > 30% of body surface

area • Extreme exertion

Reproduced with permission from Thygesen K, Alpert J, White H, et al. Universal definition of myocardial infarction. Circulation. 2007;116:2634 – 2653.

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injury is elevated in a variety of situations other than plaque rupture events. 26

Detection of recanalization after reperfusion therapy Patients who have successful reperfusion, particularly with TIMI grade 3 fl ow in the infarct-related artery, have a low mortality, an uncomplicated course and may qualify for early hospital discharge. Patients with persistent occlusion have a higher short-term mortal-ity and more complicated hospital course. It would be helpful to distinguish between these two groups of coronary occlusion patients, particularly in helping to decide if the patient with failed reperfusion from thrombolysis may need to be considered for early “rescue” angioplasty. A variety of biomarkers have been tried in this area. Early peaking of most of them is associated with reperfusion. However, none of the approaches has been capable of distinguishing TIMI 2 from TIMI 3 fl ow, which is an important distinction. 54 Thus, when thrombolysis is employed in the absence of complete or nearly complete (at least 70%) resolu-tion of ST- segment change, early coronary angiogra-phy is suggested.

Measurement of infarct size The classic studies of Shell and Sobel in the mid-1970s demonstrated that cumulative creatine kinase release (total CK or CK-MB) correlated accurately with postmortem estimates of infarct size. 55 This was demonstrated to correlate well with short- and long-term prognosis. However, this approach is confounded by reperfusion due to changes in the release ratio (the amount of protein found in the blood compared to that depleted from the heart) associated with coro-nary reperfusion. 56,57 Recent data suggest that cTn val-ues during the fi rst 4 days, but particularly at 72 – 96 hours, correlate highly with cMR determinations of infarct size, especially in patients with STEMI. 58,59 These correlations are better than those seen with other biomarkers.

Detection of reinfarction Identifi cation of reinfarction is diffi cult with all mark-ers when the values are substantially elevated. Recent data suggest that cTn measurements are capable of making the diagnosis of reinfarction when necessary and given the increased sensitivity of cTn, it likely would be much better. 23,24,60

Special situations The high specifi city of cTn for myocardial necrosis makes is very helpful in making the diagnosis of peri-operative myocardial infarction.

Elevations in cTn can occur due to plaque rup-ture events, termed “type I AMI” by the most recent guidelines. 24 However, cTn is often elevated when there are supply – demand abnormalities such as seen

with marked tachycardia or bradycardia, hypo- or hy-pertension in patients with coronary artery disease. This has been called a type 2 AMI. 24 It is often diffi -cult to distinguish these types, but it appears that these are the most common type in the perioperative situ-ations and in patients who are critically ill. They are associated with an adverse prognosis since they mark patients with CAD, 61,62 but probably do not require the same immediate care (anticoagulation, IIB/IIIA antiplatelet agents, and urgent intervention). Thus, clinical judgment is required to distinguish these types of patients from those who have type I AMI. Eleva-tions of troponin can occur due to supply – demand ab-normalities in the absence of coronary artery disease (fi xed or dynamic), especially in critically ill patients; and in these situations the diagnosis of AMI is prob-ably not appropriate. They also can occur due to drug toxicity or direct toxic effects related to the underlying abnormality or the therapy that is employed, e.g. cat-echolamines. 27 Regardless of the etiology of these el-evations, they appear to be associated with an adverse prognosis. How best to treat such patients is unclear but common sense risk factor reduction is probably indicated.

Elevations of cTn occur in patients after PCI and have led to an entity known as peri-procedural AMI. The prognosis of these patients has been shown in some studies to be similar to that of patients with spontaneous infarction. 63, 64 Unfortunately, the initial studies used either CK-MB or high cut-off values of cTn. When one uses the recommended value (the 99th percentile value), it becomes clear that most of the el-evations touted to be of importance post-PCI are as-sociated with elevations of cTn preprocedure. 65,66 In that situation, it is the preprocedure value that conveys the adverse prognosis and not the postprocedure val-ues. Indeed, it is likely that for many patients, what is being observed postprocedure is the natural rise in cTn from the index event. It is diffi cult, perhaps impossible, to know whether there is an additional component due to the PCI itself. These facts were obfuscated initially by the use of an insensitive marker, CK-MB, and then by the use of inappropriately high cut off values for cTn. If one has a normal baseline cTn preangiogra-phy, one can use cTn to detect whether injury has oc-curred post-PCI, and a value of a threefold increase has been suggested based on convention. 24 However, the prognostic importance of such elevations is modest to non-existent and, when seen at all, is seen when overt problems occur. 65,66 An additional category is recog-nized for patients who have acute stent thrombosis and who are diagnosed just as others who have spontane-ous infarctions. 24

Elevation of troponin also occurs post-cardiac sur-gery where there is always an obligatory component of cardiac injury due to direct trauma to the heart and to preservations techniques. It is clear that the higher

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the values, the worse the prognosis. 67,68 Recent cMR data suggest that most of the injury is subendocardial and apical suggesting that it is due to the techniques used surgically. 69 Higher values are seen with graft or native vessel occlusions but cut-off values to distin-guish that from the other components of injury have not thus far been developed. 70 Thus, the criteria pro-posed for the diagnosis of AMI post-cardiac surgery suggest the use of a fi vefold increase in troponin and additional imaging and/or ECG criteria. A fi vefold criteria was chosen to make sure that the diagnosis of AMI could be made in patients having off-pump procedures, where the component due to surgery and preservation is substantially less, as well as those hav-ing more complex procedures where cTn is known to be higher. 24

Late detection of infarction Recognition of recent myocardial infarction in a patient presenting several days after the onset is a relatively common clinical problem. Previously LD isoenzymes were used for this purpose, but the persistence of tro-ponin T and I for more than a week postinfarction have made those markers the markers of choice. 71

Recommendations Boxes 16.2 – 16.4 set out the recommendations from the most recent 2007 universal defi nition of AMI. 23

References 1. Lee T H , Goldman L . Serum enzyme assays in the diagnosis of

acute myocardial infarction . Ann Intern Med . 1986 ; 105 : 221 – 233 . 2. Adams III J E , Abendschein D R , Jaffe A S . Biochemical markers of

myocardial injury. Is MB creatine kinase the choice for the 1990s? Circulation . 1993 ; 88 : 750 – 763 .

3. Saenger A K , Jaffe A S . Requiem for a heavyweight: the demise of creatine kinase-MB . Circulation . 2008 ; 118 : 2200 – 2206 .

4. Dreyfus J C , Schapira G , Resnais J , Scebat L . Serum creatine kinase in the diagnosis of myocardial infarct . Rev Fr Etud Clin Biol . 1960 ; 5 : 386 – 390 .

5. Roberts R , Gowda K S , Ludhrook P A , Sobel B E . Specificity of elevated serum MB creatine phosphokinase activity in the diagnosis of acute myocardial infarction . Am J Cardiol . 1975 ; 36 : 433 – 437 .

6. Clark G L , Robinson A K , Gnepp D R , Roberts R , Sobel B E . Effects of lymphatic transport of enzyme on plasma creatine kinase time activity curves after myocardial infarction in dogs . Circ Res . 1978 ; 43 : 162 – 169 .

7. Sobel B E , Markham R P , Karlsherg R P , Roberts R . The nature of disappearance of creatine kinase from the circulation and its influence on enzymatic estimation of infarct size . Circ Res . 1977 ; 41 : 836 – 844 .

8. Vatner S F , Baig H , Manders W T , Maroko P R . Effects of coronary artery reperfusion on myocardial infarct size calculated from creatine kinase . J Clin Invest . 1978 ; 61 : 1048 – 1056 .

9. Jaffe A S , Garfinkel B T , Ritter C S , Sobel B E . Plasma MB creatine kinase after vigorous exercise in professional athletes . Am J Cardiol . 1984 ; 53 : 856 – 858 .

10. El Allaf M , Chapelle J , El Allaf D , Adam A , Faymonville M , Laurent P , Hengshem C . Differentiating muscle damage from myocardial injury by means of the serum creatine kinase (CK) isoenzyme MB mass measure/total CK activity ratio . Clin Chem . 1986 ; 32 : 291 – 295 .

11. Adams 3rd J E , Bodor G S , Davila-Roman V G , Delmez J A , Apple F S , Ladenson J H , Jaffe A S . Cardiac troponin I: a marker with high specificity for cardiac injury . Circulation . 1993 ; 88 : 101 – 106 .

12. Adams J E , Sicard G , Allan B T , Bridwell K H , Lenke L G , Davila-Roman V G , Bodor G S , Ladenson J H , Jaffe A S . Diagnosis of perioperative myocardial infarction with measurement of cardiac troponin I . N Engl J Med . 1994 ; 330 : 670 – 674 .

13. Adams J E , Davila-Roman V G , Bessey P Q , Blake D P , Ladenson J H , Jaffe A S . Improved detection of cardiac contusion with cardiac troponin . Am Heart J . 1996 ; 131 : 308 – 312 .

14. Apple F S , Quist H E , Doyle P J , Otto A P , Murakami M M . Plasma 99th percentile reference limits for cardiac troponin and creatine kinase MB mass for use with European Society of Cardiology/American College of Cardiology consensus recommendations . Clin Chem . 2003 ; 49 : 1331 – 1336 .

15. Wu A H , Gornet T G , Harker C C , Chen H L . Role of rapid immunoassays for urgent (“stat”) determinations” of creatine kinase isoenzyne MB . Clin Chem . 1989 ; 35 : 1752 – 1756 .

16. Eisenberg P R , Shaw D , Schaab C , Jaffe A S . Concordance of creatinine kinase-MB activity and mass . Clin Chem . 1989 ; 35 : 440 – 443 .

17. Mair J , Artner-Dworzak E , Dienstl A , et al. Early detection of acute myocardial infarction by measurement of mass concentration of creatine kinase MB . Am J Cardiol . 1991 ; 68 : 1545 – 1550 .

BOX 16.2 CRITERIA FOR SPONTANEOUS TYPE 1 AND TYPE 2 AMI

Criteria for acute myocardial infarction Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit together with evidence of ischemia with at least one of the following:

• Symptoms of ischemia • ECG changes of new ischemia (new ST-T changes or

new LBBB) • Development of pathological Q waves • Imaging evicence of new loss of variable myocardium

or new regional wall motion abnormality Modified with permission from Thygesen K, Alpert J, White H, et al. Universal definition of myocardial infarction. Circulation. 2007;116:2634 – 2653.

BOX 16.3 CRITERIA FOR AMI AFTER PCI

Criteria for acute myocardial infarction after PCI For PCI in patients with normal baseline troponin values, elevations of biomarkers above the 99th percentile of the upper reference limit (URL) are indicative of peri-procedural necrosis. By conven-tion, increases of biomarkers > 3 × 99th percentile URL have been defi ned as PCI-related myocardial infarction. A subtype related to a documented stent thrombosis is recognized.

Modified with permission from Thygesen K, Alpert J, White H, et al. Circulation. 2007;116:2634 – 2653.

BOX 16.4 CRITERIA FOR AMI AFTER CABG

Criteria for acute myocardial infarction after cardiac surgery

For CABG in patients with normal baseline troponin values, eleva-tions of biomarkers above the 99th percentile URL are indicative of are indicative of peri-procedural necrosis. By convention, increases of biomarkers > 5 × 99th percentile URL plus either new Q waves or new LBBB, or angiographically documented new graft or native coronary artery occlusion, or imaging evidence of new loss of viable myocardium have been defi ned as CABG-related myocardial infarction.

Modified with permission from Thygesen K, Alpert J, White H, et al. Circulation. 2007;116:2634 – 2653.

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18. Jaffe A S , Serota H , Grace A , Sobel B E . Diagnostic changes in plasma creatine kinase isoforms early after the onset of acute myocardial infarction . Circulation . 1986 ; 74 : 105 – 109 .

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34. Okamatsu K , Takano M , Sakai S , et al. Elevated troponin T levels and lesion characteristics in non – ST-elevation acute coronary syndromes . Circulation . 2004 ; 109 : 465 – 470 .

35. Wong G , Morrow D , Murphy S , et al. Elevations in troponin T and I are associated with abnormal tissue level perfusion: a TACTICS-TIMI 18 substudy . Circulation . 2002 ; 106 : 202 – 207 .

36. Mair J , Artner-Dworzak E , Lechleitner P , Smidt J , Wagner I , Dienstl F , Puschendorf B . Cardiac troponin T in diagnosis of acute myocardial infarction . Clin Chem . 1991 ; 37 : 845 – 852 .

37. Bakker A J , Koelemay M J W , Gorgels J P M C , et al. Failure of new biochemical markers to exclude acute myocardial infarction at admission . Lancet . 1993 ; 342 : 1220 – 1222 .

38. Ricchiuti V , Apple F S . RNA expression of cardiac troponin T isoforms in diseased human skeletal muscle . Clin Chem . 1999 ; 45 : 2129 – 2135 .

39. Muller-Bardorff M , Hallermayer K , Schroder A , Ebert C , Borgya A , Gerhardt W , Remppis A , Zehelein J , Katus H A . Improved troponin T ELISA specific for cardiac troponin T isoform: assay development and analytical and clinical validation . Clin Chem . 1997 ; 43 : 458 – 466 .

40. Katus H A , Looser S , Hallermayer K , Remppis A , Scheffold T , Borgya A , Essig U , Geuss U . Development and in vitro characterization of a new immunoassay of cardiac troponin T . Clin Chem . 1992 ; 38 : 386 – 393 .

41. Ricchiuti V , Voss E M , Ney A , Odland M , Anderson P A , Apple F S . Cardiac troponin T isoforms expressed in renal diseased skeletal

muscle will not cause false-positive results by the second generation cardiac troponin T assay by Boehringer Mannheim . Clin Chem . 1998 ; 44 : 1919 – 1924 .

42. MacRae A R , Kavsak P A , Lustig V , Bhargava R , Vandersluis R , Palomaki G E , Yerna M J , Jaffe A S . Assessing the requirement for the 6-hour interval between specimens in the American Heart Association classification of myocardial infarction in epidemiology and clinical research studies . Clin Chem . 2006 ; 52 : 812 – 818 .

43. Kavsak P A , MacRae A R , Yerna M J , Jaffe A S . Analytic and clinical utility of a next-generation, highly sensitive cardiac troponin I assay for early detection of myocardial injury . Clin Chem . 2009 ; 55 : 573 – 577 .

44. Apple F S , Murakami M M , Pearce L A , Herzog C A . Predictive value of cardiac troponin I and T for subsequent death in end-stage renal disease . Circulation . 2002 ; 106 : 2941 – 2945 .

45. Wallace T W , Abdullah S M , Drazner M H , Das S R , Khera A , McGuire D K , et al. Prevalence and determinants of troponin T elevation in the general population . Circulation . 2006 ; 113 : 1958 – 1965 .

46. Le E H Y , Klootwijk P J , Weimar W , Zietse R . Significance of acute versus chronic troponin T elevation in dialysis patients . Nephron Clin Prac . 2004 ; 98 : c87 – c92 .

47. Jaffe A S . Chasing troponin. How low can you go if you can see the rise? . J Am Coll Cardiol . 2006 ; 48 : 1763 – 1764 .

48. McCann C J , Glover B M , Menown I B , Moore M J , McEneny J , Owens C G , et al. Novel biomarkers in early diagnosis of acute myocardial infarction compared with cardiac troponin T . Eur Heart J . 2008 ; 29 : 2843 – 2850 .

49. Eggers K , Oldgren J , Nordenskjjold A , Lindahl B . Diagnostic value of serial measurement of cardiac markers in patients with chest pain: limited value of adding myoglobin to troponin I for exclusion of myocardial infarction . Am Heart J . 2004 ; 148 : 574 – 581 .

50. Ilva T , Eriksson S , Lund J , Porela P , Mustonen H , Pettersson K , et al. Improved early risk stratification and diagnosis of myocardial infarction, using a novel troponin I assay concept . Eur J Clin Invest . 2005 ; 35 : 112 – 116 .

51. Kavsak P A , MacRae A R , Newman A M , Lustig V , Palomaki G E , Ko D T , Tu J V , Jaffe A S . Effects of contemporary troponin assay sensitivity on the utility of the early markers myoglobin and CKMB isoforms in evaluating patients with possible acute myocardial infarction . Clin Chim Acta . 2007 ; 380 : 213 – 216 .

52. Kavsak P A , MacRae A R , Palomaki G E , Newman A M , Ko D T , Lustig V , et al. Health outcomes categorized by current and previous definitions of acute myocardial infarction in an unselected cohort of troponin-naive emergency department patients . Clin Chem . 2006 ; 52 : 2028 – 2035 .

53. Anderson J L , Adams C D , Antman E M , Bridges C R , Califf R M , Casey D E J , et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction . Circulation . 2007 ; 116 : e148 – e304 .

54. Jaffe A S , Eisenberg P R , Abendschein D R . Conjoint use of MM and MB creatine kinase isoforms for detection of coronary recanalization . Am Heart J . 1994 ; 127 : 1461 – 1466 .

55. Sobel B E , Bresnahan G F , Shell W E , Yoder R D . Estimation of infarct size in man and its relation to prognosis . Circulation . 1972 ; 46 : 640 – 648 .

56. Gibbons R J , Valeti U S , Araoz P A , Jaffe A S . The quantification of infarct size . J Am Coll Cardiol . 2004 ; 44 : 1533 – 1542 .

57. Sobel B E , LeWinter M M . Ingenuous interpretation of elevated blood levels of macromolecular markers of myocardial injury: a recipe for confusion . J Am Coll Cardiol . 2000 ; 35 : 1355 – 1358 .

58. Vasile V C , Babuin L , Giannitsis E , Katus H A , Jaffe A S . Relationship of MRI-determined infarct size and cTnI measurements in patients with ST-elevation myocardial infarction . Clin Chem . 2008 ; 54 : 617 – 619 .

59. Giannitsis E , Steen H , Kurz K , Ivandic B , Simon A C , Futterer S , et al. Cardiac magnetic resonance imaging study for quantification of infarct size comparing directly serial versus single time-point measurements of cardiac troponin T . J Am Coll Cardiol . 2008 ; 51 : 307 – 314 .

60. Apple F S , Murakami M M . Cardiac troponin and creatine kinase MB monitoring during in-hospital myocardial reinfarction . Clin Chem . 2005 ; 51 : 460 – 463 .

61. Guest T M , Ramanathan A V , Schechtman K B , Ladenson J H , Jaffe A S . Myocardial injury in critically ill patients: A surprisingly frequent complication . JAMA . 1995 ; 273 : 1945 – 1949 .

62. Babuin L , Vasile V C , Rio Perez J A , Alegria J R , Chai H S , Afessa B , Jaffe A S . Elevated cardiac troponin is an independent risk factor for short- and long-term mortality in medical intensive care unit patients . Crit Care Med . 2008 ; 36 : 759 – 765 .

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63. Califf R M , Abdelmeguid A E , Kuntz R E , Popma J J , Davidson C J , Cohen E A , et al. Myonecrosis after revascularization procedures . J Am Coll Cardiol . 1998 ; 31 : 241 – 251 .

64. Brener S J , Lytle B W , Schneider J P , Ellis S G , Topol E J . Association between CK-MB elevation after percutaneous or surgical revascularization and three-year mortality . J Am Coll Cardiol . 2002 ; 40 : 1961 – 1967 .

65. Miller W L , Garratt K N , Burritt M F , Lennon R J , Reeder G S , Jaffe A S . Baseline troponin level: key to understanding the importance of post-PCI troponin elevations . Eur Heart J . 2006 ; 27 : 1061 – 1069 .

66. Prasad A , Rihal C S , Lennon R J , Singh M , Jaffe A S , Holmes D R J . Significance of periprocedural myonecrosis on outcomes after percutaneous coronary intervention . Circ Cardiovasc Intervent . 2008 ; 1 : 10 – 19 .

67. Januzzi J L , Lewandrowski K , MacGillivray T E , Newell J B , Kathiresan S , Servoss S J , Lee-Lewandrowski E . A comparison of cardiac troponin T and creatine kinase-MB for patient evaluation after cardiac surgery . J Am Coll Cardiol . 2002 ; 39 : 1518 – 1523 .

68. Croal B L , Hillis G S , Gibson P H , Fazal M T , El-Shafei H , Gibson G , et al. Relationship between postoperative cardiac troponin I levels and outcome of cardiac surgery . Circulation . 2006 ; 114 : 1468 – 1475 .

69. Selvanayagam J B , Pigott D , Balacumaraswami L , Petersen S E , Neubauer S , Taggart D P . Relationship of irreversible myocardial injury to troponin I and creatine kinase-MB elevation after coronary artery bypass surgery: insights from cardiovascular magnetic resonance imaging . J Am Coll Cardiol . 2005 ; 45 : 629 – 631 .

70. Thielmann M , Massoudy P , Marggraf G , Knipp S , Schermund A , Piotrowski J , Erbel R , Jakob H . Role of troponin I, myoglobin, and creatine kinase for the detection of early graft failure following coronary artery bypass grafting . Eur J Cardiothor Surg . 2004 ; 26 : 102 – 109 .

71. Jaffe A S , Landt Y , Parvin C A , Abendschein D R , Geltman E M , Ladenson J H . Comparative sensitivity of cardiac troponin I and lactate dehydrogenase isoenzymes for the diagnosing acute myocardial infarction . Clin Chem . 1996 ; 42 : 1770 – 1776 .

1

40 • Intravenous heparin, low-molecular-weight heparins, and thrombin antagonists

40 Intravenous heparin, low-molecular-weight heparins, and thrombin antagonists

Keith Fox and Peter Thompson

Thrombin, also known as activated factor II (IIa), converts fi brinogen to an active form that assembles into fi brin. After injury to a vessel wall, tissue factor is exposed on the surface of the damaged endothelium. Interaction of tissue factor with plasma factor VII acti-vates the coagulation cascade, producing thrombin by stepwise activation of factors V, VIII, and XI, which generates more thrombin. By activating factor XIII, thrombin favors the formation of cross-linked bonds among the fi brin molecules, stabilizing the clot (see Fig 40.1 ).

Thrombin is also a very potent stimulator of platelet aggregation and it contributes to the infl ammatory cas-cade by enhancing cytokine release. The central role of thrombin as a regulator of thrombosis makes the antithrombin agents essential tools in the management of coronary thrombosis. This chapter discusses the use of unfractionated heparin, low molecular weight hepa-rins, factor Xa inhibitors, and direct antithrombins. Each affects thrombin action in different ways.

UNFRACTIONATED HEPARIN

Mode of action The action of thrombin is counteracted by antithrombin III, now known as antithrombin (AT), and heparin pro-duces a conformational change that converts AT from a slow, progressive thrombin inhibitor to a very rapid inhibitor of thrombin and factor Xa. 1 Unfractionated heparin (UFH) is a heterogeneous mixture of polysac-charide molecules, with a molecular weight ranging from 2000 to 30,000 (mostly 15 – 18,000) daltons (see Table 40.1 ).

Most co mmercial heparin is derived from porcine intestinal mucosa and is a polymer of alternating D-glucuronic acid and N -acetyl-D-glucosamine residues. One-third of the molecules found within a standard UFH preparation contain the relevant pentasaccharide sequence that binds to antithrombin and accelerates the rate at which antithrombin inhibits factor Xa (see Fig 40.2 ).

Although inhibition of Xa activity reduces the generation of thrombin, inactivation of pre-formed thrombin requires the action of direct antithrombins or inhibition with agents that act on factor IIa. This re-quires heparin to bind to both thrombin and antithrom-bin and to bridge them, requiring at least 18 saccharide units to provide suffi cient length to bridge to factor IIa. The formation of a ternary complex between AT,

Withoutheparin

Heparin

Heparin

+

ClottingenzymeATIII

ATIII

ATIII

Clottingenzyme

Clottingenzyme

Ternary complexformation

Dissociation ofheparin

Figure 40.1 Action of heparin in blocking action of antithrombin III (ATIII). Reproduced with permission from Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin mechanisms of action, pharmacokinetics, dosing, monitoring, effi cacy, and safety. Chest. 2001;119:64S – 94S.

Table 40.1 Molecular weights of the commonly used parenteral antithrombins.

Antithrombin Mol ecular weight

Number of saccharide units

Anti-Xa * to anti-IIa activity

Unfraction-ated heparin (heparin)

15,000 – 30,000

18 1.0:1.0

Dalteparin (fragmin)

6,000 15 2.7:1.0

Enoxaparin (Lovenox, Clexane)

4,200 15 3.8:1.0

Fondaparinux 1,728 5 Anti-Xa only. No anti-IIa activity

2

SECTION 5 • DRUG THERAPIES

(a) Unfractionatedheparin

(b) Low-molecular-weight heparin

(c) Pentasaccharide

Pentasaccharidesequence

Factor Xa

Thrombin

Antithrombin

Figure 40.2 Mechanism of action of heparin, low-molec-ular-weight heparin (LMWH), and fondaparinux, a synthetic pentasaccharide. (a) Heparin binds to antithrombin via its pentasaccharide sequence. This induces a conformational change in antithrombin facilitating its interaction with factor Xa. To achieve thrombin inhibition, heparin must bind to both antithrombin and thrombin. To perform this bridging function, heparin chains of at least 18 saccharide units are required. With a mean molecular weight of 15,000, all of the heparin

chains are long enough to do this. (b) LMWH potentiates factor Xa inhibition by antithrombin, because with a mean molecular weight of 4500 – 5000, at least half of the LMWH chains are too short to bridge antithrombin to thrombin. (c) The pentasaccharide accelerates factor Xa inhibition by anti-thrombin only because it is too short to bridge antithrombin to thrombin. Reproduced with permission from Fauci AS, et al. Har-rison’s textbook of internal medicine. 17th edn. New York: McGraw-Hill Companies; 2009.

3


thrombin, and heparin results in the inactivation of thrombin. After the binding of AT to thrombin, the heparin can uncouple from the complex and be reuti-lized. Heparin has equal capacity to promote the inhi-bition of thrombin and factor Xa by antithrombin and is assigned an anti-factor Xa to anti-factor IIa (throm-bin) ratio of 1:1.

Method of administration Heparin is given parenterally, as it is degraded when taken by mouth. It can be injected intravenously or subcutaneously. When injected subcutaneously, the initial dose must be chosen to overcome the lower bio-availability with this route. 2 Intramuscular injections (injections into muscle) are avoided because of the potential for hematoma formation.

Monitoring of effect The duration of action for heparin is variable 3 and requires monitoring of its effect. Patient-to-patient vari-ation in antithrombin activity and the induction of hep-arin-binding proteins as part of an acute phase reaction mean that heparin dosage must be individually moni-tored and adjusted. Even with careful attention to detail in trial settings, studies have shown that optimal hepa-rin control is achieved only in a minority of patients. The methods of monitoring heparin activity include: • activated partial thomboplastin time . This is the

usual method of monitoring. 4 The therapeutic win-dow for UFH is narrow, requiring frequent moni-toring of the activated partial thromboplastin time (APTT).

• activated clotting time . For high-dose heparin, which requires rapid bedside monitoring and fre-quent adjustment of dose, the activated clotting time (ACT) is used. 5

Dose of UFH

n past years, a widely used, easily remembered regi-men has been to use a bolus of 5000 U followed by 1000 U per hour. In recent years, the importance of using a weight-adjusted dose of UFH to reduce the risk of bleeding has been recognized. 6 In acute coro-nary syndromes, an initial bolus of 60 – 70 IU/kg with a maximum of 5000 IU, followed by an infusion of 12 – 15 IU/kg/hour, to a maximum of 1000 IU/hour is recommended in Europe, 7 and in the USA an initial bolus of 60 U per kg (maximum 4000 U) and an initial infusion of 12 U per kg per hour (maximum 1000 U per hour). 8 The optimal target level of APTT in acute coronary syndromes is 50 – 70 s, corresponding to 1.5 – 2.5 times the upper limit of normal. 9 The basis for this recommendation is shown in Figure 40.3 .

In percutaneous coronary intervention (PCI), the recommended doses after uncomplicated PCI is a weight-adjusted heparin bolus of 60 to 100 IU/kg to produce a target ACT of 250 to 350s in patients not

receiving a glycoprotein IIb/IIIa inhibitor, and a heparin bolus of 50 – 70 IU/kg to achieve a ACT > 200 s in patients receiving a glycoprotein IIb/IIIa inhibitor, and no routine post-procedural infusion of heparin. 10

Effi cacy

UFH in acute coronary syndromes

The evidence base for the use of heparin in unstable angina and non-ST-elevation myocardial infarction (MI), surprisingly for such a widely used drug, is

30

5%

4%

3%

2%

1%

0%50 70 90 110 130

Pro

bab

ility

of

rein

farc

tio

n

APTT (seconds) at 12 hours150

30

8%

6%

4%

2%

0%50 70 90 110 130

Pro

bab

ility

of

dea

th


30

19%

17%

15%

13%

11%

9%

7%

5%50 70 90 110 130

Pro

bab

ility

of

mo

der

ate

or

seve

re b

leed

ing


Figure 40.3 Risk of major bleeding and probability of reinfarction and death in relation of APTT at 24 hours after thrombolytic therapy. Data from the GUSTO trial. Reproduced with permission from Granger CB, Hirsh J, Califf RM, et al. for the GUSTO-I Investigators. Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction. Circulation. 1996;93:870 – 878.

4


relatively sparse and based on clinical trials with fewer than 1000 patients in total. 7,8 Meta-analyses of these trials of short-term UFH vs. placebo or untreated con-trols showed a signifi cant risk reduction for death or MI of 33 – 54% ( p = 0.016), 11,8 depending on the time of the end point. The risk reduction for MI accounted for practically all of the benefi cial effect. The evidence for benefi t in aspirin-treated patients is limited to small studies but a pooled analysis suggests benefi t (OR 0.67, 95% CI 0.45 – 0.99, p = 0.045). 11

UFH in STEMI

Most of the randomized trials of the value of hepa-rin in conjunction with thrombolytic therapy were conducted before the routine use of aspirin. An over-view of these studies showed that UFH was associ-ated with a 23% reduction in mortality and an 18% reduction in risk of reinfarction. 12 Heparin is used as an adjunct to fi brinolytic therapy as there is activa-tion of plasmin by the lytic agents, which activates thrombin. 13 The ISIS III 14 and GISSI 15 trials evalu-ated the role of subcutaneous heparin after streptoki-nase and showed only a marginal benefi t on mortality and an increased risk of bleeding. Heparin after r-TPA helps to maintain coronary patency, 16,17 but overviews of trials of heparin with thrombolytic therapy con-cluded that there was only a marginal benefi t on isch-emic outcomes and an increased risk of bleeding. 18 In the absence of convincing evidence, it is reasonable to continue UFH for at least 48 hours after fi brino-lysis with fi brin-specifi c agents (alteplase, reteplase, tenecteplase) and to target the APTT to 1.5 to 2.0 times control (approximately 50 to 70 seconds), and to avoid its use after streptokinase except in patients with an unstable course.

Since it has long been established that the risk of stroke after STEMI is dependent on the size of the in-farction, 19 heparin (and subsequent oral anticoagulation) should be considered in patients with large, especially anterior, STEMIs. A randomized trial of IV followed by subcutaneous UFH reduced the risk of death and stroke in patients with extensive infarction. 20 The risk from deep venous thrombosis (DVT) in post-STEMI patients was higher in past years when patients with MI were treated with prolonged bed rest, and subcutaneous UFH had been used in doses of 5000 U twice daily. 21 The ra-tionale for this is less pressing now with routine aspirin and shorter bed stays, but heparin for prevention of DVT may be appropriate in the post-STEMI patient who may have a prolonged bed stay for concomitant illness or have a past history of DVT. In current practice, enoxa-parin (see below) is usually chosen for the prevention of DVT.

UFH in PCI

Intravenous UFH is used routinely during percutane-ous coronary intervention 10 and the dose is monitored

using the ACT as outlined above. There is a correlation between the level of ACT achieved during the proce-dure and subsequent ischemic complications. 22 Routine post-PCI heparin infusion is no longer recommended as it has been shown to increase the risk of bleeding without improving ischemic complications. 23

Heparin resistance

Some patients require higher doses than usual to achieve therapeutic levels of APTT. If the daily dose to achieve therapeutic levels exceeds 35,000 U, the patient is designated as being “heparin resistant”. The reasons include variations in antithrombin levels and heparin binding proteins. In such patients, monitor-ing of heparin activity with anti-Xa levels rather than APTT may be required, 24 but the use of a low molecu-lar weight heparins or a direct antithrombin in this set-ting avoids the diffi culty with control of UFH.

Limitations of unfractionated heparin

Heparin has variable bioavailability at low doses, has a variable anticoagulant activity because of binding to plasma proteins, and is unable to inhibit factor Xa when it is bound to the fi brin clot. Factor Xa bound to activated platelets within platelet-rich thrombi has the potential to generate thrombin, despite heparin. Once this thrombin binds to fi brin, it too is protected from inhibition by the heparin-antithrombin complex and the thrombin can promote further clotting by locally activating platelets. Prolonged infusion of heparin can lead to heparin-induced thrombocytopenia, but this can occasionally occur early if there has been expo-sure to heparin within the previous 3 months. Very prolonged administration of heparin can cause osteo-porosis.

Practical aspects of using unfractionated heparin

In cardiology practice, subcutaneous UFH has been supplanted by subcutaneous low molecular weight heparins, predominantly enoxaparin. Therefore, the intravenous route is the preferred route of adminis-tration for UFH. Heparin can be diluted in saline or 5% dextrose; 25,000 U heparin in 500 mL achieves a solution of 50U/mL. An infusion pump greatly assists in achieving a consistent infusion rate and should be used where possible. To monitor for possible heparin induced thrombocytopenia, a platelet count should be obtained at baseline and after 3 days if the hepa-rin infusion continues. The fi rst APTT after the load-ing dose should be taken at about 6 hours and this level used for the subsequent calculation of the rate of infusion. Thereafter, monitoring of APTT levels should be done at least 12 hourly, and the UFH dose adjusted. Prolonged administration is rarely necessary and should be avoided to limit the risk of bleeding and other complications. Switching between UFH and low molecular weight heparin can result in the patient

5


being exposed to both agents simultaneously and increase the risk of bleeding: it requires special pre-cautions (see below). In the event of accidental over-dose, withdrawal of the infusion is usually suffi cient. If associated with severe bleeding, protamine can be given in a dose of 1mg per 100U of heparin. Rapid injection of high doses of protamine can cause hypo-tension. The APTT can be re-measured after the initial bolus of protamine and further doses can be given to a maximum of 50 mg.

Heparin hypersensitivity

During 2007, a series of severe, some fatal, allergic reactions to heparin led to withdrawal of the drug in several countries. The manufacturing process for some heparins was found to include a hyper sulfated form of chondroitin, which had the capacity to activate the contact coagulation system, leading to bradykinin and activation of complement. 25 Changes to the manufac-turing process overcame the problem.

LOW-MOLECULAR-WEIGHT HEPARINS Mode of action Low-molecular-weight heparins (LMWHs) also work by inactivating antithrombin. However, with a mean molecular weight of 5000, usually about 17 saccharide units, at least half of the pentasaccharide-containing chains of LMWH are too short to bridge thrombin to antithrombin. Nevertheless, they retain the capacity to accelerate factor Xa inhibition by antithrombin by bringing about a conformational changes in antithrom-bin from the pentasaccharide binding. Consequently, LMWH catalyses factor Xa inhibition by its action on antithrombin more than on thrombin inhibition. Depending on their molecular weight distributions, LMWH preparations have anti-factor Xa to anti-fac-tor IIa ratios ranging from 2:1 to 4:1. The molecular weights of the LMWHs and Xa to IIa ratios are shown in Table 40.1 and compared with UFH and pentasac-charide antithrombin.

LMWHs also have superior pharmacokinetic prop-erties with 90% bioavailability after subcutaneous in-jection due to a decreased propensity to bind to plasma proteins, endothelial cells, and macrophages. This property of the LMWHs improves their predictability of response and is probably the most relevant to their clinical effect and advantage over UFH. LMWH pro-duces a more predictable dose response, and resistance to LMWH is rare.

Method of administration With a longer half-life and more predictable anticoagu-lant response, LMWH can be given subcutaneously once or twice daily without coagulation monitoring. These properties render LMWH more convenient than unfractionated heparin. However, LMWH can be used intravenously in acute coronary syndromes or PCI.

Monitoring of response Because of the predictable response, coagulation monitoring is not needed except in patients with renal dysfunction or low body weight. 26 If monitoring is nec-essary, anti-factor Xa levels must be measured because most LMWH preparations have little effect on the APTT. Resistance to LMWHs is rare; there is a lower risk of heparin induced thrombocytopenia.

Dose The two LMWHs that have been most widely evalu-ated in the coronary care unit patients are enoxaparin and dalteparin.

Enoxaparin is administered subcutaneously twice daily for therapeutic effect. In acute coronary syn-dromes, the dose is 1 mg/kg twice daily. In patients with renal dysfunction (especially with GFR < 30 mL/min) the dose needs to be reduced and may need to be monitored with anti-Xa levels.

For prophylaxis of deep vein thrombosis, the dose is 40 mg injected once daily.

Dalteparin is also administered subcutaneously in a dose of 120 IU/kg of body weight, to a maximum of 10,000 IU, every 12 hours.

Effi cacy

LMWH in acute coronary syndromes

Both dalteparin and enoxaparin have been evaluated in detail in NSTEMI and unstable angina. Enoxaparin has not been compared against placebo, but dalteparin 120 IU was compared with placebo in the FRISC study, and showed a substantial (63%) risk reduction in death or MI during the fi rst 6 days. 27

Comparison of the LMWHs against UFH has been intensively studied in nine randomized trials in pa-tients with acute coronary syndromes. The extent of the benefi t of LMWH over UFH has been debated. Trials of dalteparin and nadroparin did not show su-periority over UFH. An overview of the 22, 000 pa-tients in the six large enoxaparin versus UFH trials in acute coronary syndromes showed that enoxaparin was more effective than unfractionated heparin in prevent-ing the combined end point of death or MI, but only just within 95% confi dence intervals (pooled OR 0.91, 95% CI 0.83 – 0.99). 28 The benefi t of enoxaparin in the comparative trials was driven largely by a reduction in non-fatal MI, and not mortality. The overview did not show an increased risk of need for transfusion or major bleeding. The major bleeding risk in the two major tri-als, ESSENCE 29 and TIMI 11B, 30 was not signifi cantly worse with enoxaparin, although there were some in-creases in minor bleeding.

These results, together with the lack a need for of coagulation monitoring, have led to widespread recom-mendation and uptake of enoxaparin in acute coronary syndromes. 8 A retrospective analysis of a major trial

6


of enoxaparin versus UF heparin for PCI suggested a signifi cant increase in bleeding risk when the agents were switched. 31

LMWH in STEMI

LMWH can be used as an alternative to UFH in the patient thought to be at high risk of reocclusion. The data from a trial of 20,000 patients in STEMI treated with fi brinolytics showed that enoxaparin was superior to UFH as adjunctive treatment for fi brinolysis. There was a reduction in non-fatal reinfarction, a neutral effect on deaths, but a signifi cant increase in bleed-ing in the patients treated with enoxaparin. 32,33 In the patients in the trial who subsequently underwent PCI, there was no increase in bleeding in the enoxaparin group 34 (these patients were maintained on enoxapa-rin for the PCI and not “crossed over” to UFH). UFH or LMWH are alternatives in patients at high risk of thromboembolic complications.

LMWH in PCI

Intravenous enoxaparin can be used instead of UFH in patients having PCI. If the last dose of enoxaparin is administered between 8 hours and 12 hours before PCI, the recommended dose is 0.3 mg/kg bolus of IV enoxaparin at the time of PCI. If the last enoxaparin dose is administered more than 12 hours before PCI, conventional anticoagulation therapy during PCI is recommended. 10

Practical aspects of using LMWH

While the twice-daily subcutaneous regimen without coagulation monitoring with enoxaparin is convenient, careful attention needs to be paid to the method of admin-istration to avoid abdominal bruising and increased risk of more signifi cant bleeding. This is particularly the case when fi brinolytic and other antithrombotic agents are being used in the same patient. It is recommended that the external surface of the needle be free of excess enoxaparin at the time of injection (the usual needle fl ush should be done with care to bring the drug to the tip of the needle but not spill over), and local pressure be applied to the site of the injection for 5 minutes fol-lowing the injection. Although it is possible to achieve a hematoma-free groin site in patients undergoing cath-eterization or PCI in patients on enoxaparin, the morn-ing dose should be avoided on the day of catheterization. Particular precautions to avoid bleeding are necessary in patients who have renal dysfunction or who are being switched between UFH and enoxaparin. To reduce the risk of bleeding, it is preferable to continue the same agent once a patient has been commenced on enoxaparin or UFH, rather switching between agents.

FACTOR Xa INHIBITORS Fondaparinux is a synthetic analog of the antithrom-bin-binding pentasaccharide sequence.

Mode of action Fondaparinux binds only to antithrombin (Factor Xa) and is too short to bridge thrombin to antithrombin. It has a number of features that make it potentially superior to LMWH. It is 100% bioavailable after a subcutaneous injection and has a long plasma half-life of 17 hours.

Method of administration Subcutaneous once daily.

Monitoring of response None needed.

Dose The usual dose is 2.5 mg per day. It is cleared unchanged via the kidneys, so is contraindicated in patients with a creatinine clearance < 30 mL/min and should be used with caution in those with a creatinine clearance < 50 mL/min.

Effi cacy

Fondaparinux in acute coronary syndromes

Fondaparinux 2.5 mg per day was compared with enoxa-parin 1 mg twice daily in patients with acute coronary syndrome primarily being treated with a conservative (limited use of PCI) approach. 35 The trial was designed as a non-inferiority comparison of the two antithrom-botic strategies. Neither enoxaparin nor fondaparinux were inferior to each other for the major endpoint of the study of death, myocardial infarction, or refractory ischemia. However, there was an unexpected fi nding of lower risk of death, and a striking halving of the risk of major bleeding in the fondaparinux group. Although the protocol favored a conservative approach, there was an unacceptable increase (three times greater) in the number of catheter thromboses in the patients having coronary angiography or PCI. The OASIS 5 and 6 trials showed an excess of catheter related thrombus, in the context of PCI. Hence, fondaparinux is not recommended in cur-rent guidelines for primary PCI for ST-elevation MI. 36,37 For non-ST-elevation acute coronary syndrome and PCI the European Guidelines recommend additional UFH in standard dose (50 – 100 IU/kg bolus) in addition to fondaparinux, 7 (the addition of UFH to fondaparinux did not increase bleeding risks in OASIS. 5,6

Fondaparinux in STEMI

Fondaparinux was evaluated in STEMI patients by comparing it with placebo when there was no heparin indication, and against UFH when there was. There was a signifi cant benefi t on both death and reinfarction in comparison with placebo (principally patients treated with streptokinase or no fi brinolytic). The effect was not seen in patients who underwent PCI, 38 and in the stratum of patients who received heparin (principally with fi brin specifi c fi brinolytic agents), the infl uence

7


on effi cacy end points was not signifi cantly different, but bleeding was less frequent with fondaparinux.

DIRECT ANTITHROMBINS Direct thrombin inhibitors do not require a plasma cofactor and bind directly to thrombin and block its interaction with its substrates. They have the advan-tage over heparins and factor Xa inhibitors of being able to inhibit thrombin that is bound to fi brin or fi brin degradation products. Because of these advantages, there was great enthusiasm for the use of recombi-nant hirudin analogs in acute coronary syndromes in the 1990s. However, the results, particularly from the large GUSTO II trial, 39 were disappointing. A meta-analysis of these trials showed an improvement in death and myocardial infarction, although this was only marginally signifi cant at 30 days. 40 Analysis of the effect of univalent versus bivalent analogs showed increased bleeding for univalent agents (hirudin) and a suggestion of reduced bleeding with bivalent agents (bivalirudin). Therefore the univalent hirudin analogs (lepirudin and desirudin) are not used in acute coronary syndromes, although they have a role in the treatment of heparin-induced thrombocytopenia. 41 Of the direct antithrombins, bivalirudin is the most promising.

Bivalirudin

Mode of action

Bivalirudin has a dual effect on binding to the two rel-evant sites on the surface of the thrombin molecule. It has undergone a name change from Hirulog, when fi rst introduced, to bivalirudin. The initial evaluation was in ST-elevation MI, when the drug was known as hirulog and was administered with streptokinase: the HERO trial. 42 See Figure 40.4 for the interaction of heparin, antithrombin, thrombin and direct thrombin inhibitors.

Method of administration

The drug is administered intravenously by fast injec-tion followed by an infusion.

Monitoring of response

Because all thrombin-dependent coagulation assays are affected, thrombin times are not helpful in monitor-ing bivalirudin activity. Bivalirudin can be monitored with the use of the activated clotting time. Although there is no need for routine monitoring, due to the pre-dictable anticoagulant activity of bivalirudin, the lack of an antidote for rapidly reversing the effects of direct thrombin inhibitors means monitoring these drugs is of importance for patients who have high risk of bleeding, such as patients with renal impairment.

Dose

As an anticoagulant for patients undergoing PCI bivalirudin therapy is commenced with an initial IV

loading dose (fast injection) of 0.75 mg/kg; an ACT should be performed 5 minutes after the bolus dose of bivalirudin has been administered, and an additional bolus of 0.3 mg/kg be given if needed. The loading dose is followed by IV infusion at a rate of 1.75 mg/kg per hour continued throughout the procedure, and for up to 4 hours post-procedure. After 4 hours, an additional IV infusion of bivalirudin may be initiated at a rate of 0.2 mg/kg per hour for up to 20 hours. If the creatinine clearance is less than 30 mL/minute, reduction of the infusion rate to 1 mg/kg/hour should be considered.

Effi cacy

Bivalirudin in acute coronary syndromes The initial evaluation of bivalirudin in non-ST-eleva-tion acute coronary syndromes showed similar out-comes for ischemic complications when compared with unfractionated heparin, and a lower bleeding risk. 43 Subsequent evaluation in a larger trial in which PCI was planned 44 compared heparin with bivaliru-din in patients having glycoprotein IIb/IIIa inhibition and heparin with bivalirudin with glycoprotein IIb/IIIa inhibitor added only as necessary. In the glycoprotein IIb/IIIa inhibitor groups, bivalirudin was equivalent to heparin for ischemia, bleeding, and clinical outcomes. Bivalirudin alone compared with heparin plus gly-coprotein IIb/IIIa inhibitors was equivalent for isch-emia, but there was a halving of major bleeding and superior 30-day net clinical outcomes. The fi ndings of equivalent ischemic outcomes and lower bleeding risk were confi rmed in the patients undergoing PCI, 45 and 1-year follow-up has confi rmed equivalent ischemic outcomes. 46 The results clearly suggest a lower bleed-ing risk with bivalirudin. However, the complexities of interaction with other antithrombotic agents intro-duce some uncertainty in interpreting these results. For instance, the group who did not receive a thienopyri-dine prior to bivalirudin had a trend to more frequent ischemic complications. 8 Nevertheless, thienopyri-dines are now part of the standard treatment regimen (see Ch 42) and are recommended in international guidelines.

Bivalirudin in STEMI The use of bivalirudin as compared with heparin plus glycoprotein IIb/IIIa inhibitors in patients with acute ST-elevation MI undergoing PCI showed signifi cantly lower 30-day mortality and highly signifi cant reduc-tions in bleeding risk. 47

Bivalirudin in PCI Bivalirudin has been evaluated in detail in patients undergoing PCI. The fi ndings of similar ischemic out-comes with reduced bleeding risk have been confi rmed in two large trials compared with heparin 48 and with heparin plus glycoprotein IIb/IIIa inhibitors. 49

8


Practical aspects of using bivalirudin The bivalirudin dose needs to be adjusted for patients with renal dysfunction. There are several incompat-ibilities relevant to the coronary care unit: alteplase, reteplase, streptokinase or amiodarone should not be co-administered through the same IV infusion. In con-trast to the apparent increase in bleeding in switching from enoxaparin to heparin, switching from UFH or enoxaparin to bivalirudin results in comparable isch-emic outcomes, and a 50% reduction in major bleed-ing. 50

Oral antithrombins The role of novel oral antithrombin, anti-factor Xa inhibitors and thrombin-receptor antagonists is under

active investigation in acute coronary syndromes. Dabigatran is an orally active direct antithrombin with promising properties, reaching peak plasma con-centrations and onset of anticoagulant effect within 0.5 – 2 hours after administration. 51 It has recently been shown to be equivalent to warfarin in the prevention of stroke in atrial fi brillation with lower risk of hemor-rhage. 52 Selective direct inhibitors of factor Xa includ-ing rivaroxaban have been shown to be effective in venous thromboembolism and have shown suffi ciently encouraging results in phase II studies in acute coro-nary syndromes to progress to a phase III trial. 53 An orally active thrombin receptor antagonist drug have been evaluated in a phase II trial in PCI patients with encouraging antithrombotic effects without increase in

srotibihni nibmorht tceriDnirapeH

srotibihni nibmorht tceriDnirapeH

Fibrin-bound thrombin

Soluble thrombin

Antithrombin

Antithrombin

Thrombin

Fibrin-boundthrombin

Fibrin-boundthrombin

Fibrin

Fibrin

Fibrin

Thrombin

Thrombin

Exosite 2

Exosite 2

Exosite 1

Exosite 1

Active site

Active site

Univalent directthrombin inhibitor

Univalent directthrombin inhibitor

Bivalent directthrombin inhibitor

Bivalent directthrombin inhibitor

Heparin

Heparin

Figure 40.4 Interaction of heparin, antithrombin, thrombin and direct thrombin inhibitors. Reproduced with permission from De Nisio M, Middeldor S, Buller HR. Direct thrombin inhibitors. New Engl J Med 2005;353:1028 – 1040.

9


bleeding, even with potent antiplatelet therapy. 54 Each of these drugs is currently under evaluation to assess its role in acute coronary syndromes.

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Raschke R , et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety . Chest . 2001 ; 119 ( 1 Suppl ) : 64S – 94S .

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13. Eisenberg P R . Role of heparin in coronary thrombolysis . Chest . 1992 ; 101 : 131S – 139S .

14. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group . ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction . Lancet . 1992 ; 339 : 753 – 770 .

15. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico . GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction . Lancet . 1990 ; 336 : 65 – 71 .

16. Thompson P L , Aylward P E , Federman J , Giles R W , Harris P J , Hodge R L , et al. A randomized comparison of intravenous heparin with oral aspirin and dipyridamole 24 hours after recombinant tissue-type plasminogen activator for acute myocardial infarction. National Heart Foundation of Australia Coronary Thrombolysis Group . Circulation . 1991 ; 83 : 1534 – 1542 .

17. Hsia J , Hamilton W P , Kleiman N , Roberts R , Chaitman B R , Ross A M . A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. Heparin-Aspirin Reperfusion Trial (HART) Investigators . N Engl J Med . 1990 ; 323 : 1433 – 1437 .

18. Mahaffey K W , Granger C B , Collins R , O’Connor C M , Ohman E M , Bleich S D , et al. Overview of randomized trials of intravenous heparin in patients with acute myocardial infarction treated with thrombolytic therapy . Am J Cardiol . 1996 ; 77 : 551 – 556 .

19. Thompson P L , Robinson J S . Stroke after acute myocardial infarction: relation to infarct size . Br Med J . 1978 ; 2 : 457 – 459 .

20. The SCATI (Studio sulla Calciparina nell’Angina e nella Trombosi Ventricolare nell’Infarto) Group . Randomised controlled trial of subcutaneous calcium-heparin in acute myocardial infarction . Lancet . 1989 ; 2 : 182 – 186 .

21. Chesebro J H , Fuster V . Antithrombotic therapy for acute myocardial infarction: mechanisms and prevention of deep venous, left ventricular, and coronary artery thromboembolism . Circulation . 1986 ; 74 : III1 – III10 .

22. Chew D , Bhatt D , Lincoff A , et al. Defining the optimal activated clotting time during percutaneous coronary intervention: aggregate results from 6 randomized, controlled trials . Circulation . 2001 ; 103 : 961 – 966 .

23. Friedman H Z , Cragg D R , Glazier S M , et al. Randomized prospective evaluation of prolonged versus abbreviated intravenous heparin therapy after coronary angioplasty . J Am Coll Cardiol . 1994 ; 24 : 1214 – 1219 .

24. Levine M N , Hirsh J , Gent M , et al. A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin . Arch Intern Med . 1994 ; 154 : 49 – 56 .

25. Kishimoto T K , et al. Contaminated heparin associated with adverse clinical events and activation of the contact system . N Engl J Med . 2008 ; 358 : 2457 – 2467 .

26. Weitz J I . Low-molecular-weight heparins . N Engl J Med . 1997 ; 337 : 688 – 698 .

27. Fragmin during Instability in Coronary Artery Disease (FRISC) Study Group . Low-molecular-weight heparin during instability in coronary artery disease . Lancet . 1996 ; 347 : 561 – 568 .

28. Petersen J L , Mahaffey K W , Hasselblad V , Antman E M , Cohen M , Goodman S G , et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-segment elevation acute coronary syndromes: a systematic overview . JAMA . 2004 ; 292 : 89 – 96 .

29. Cohen M , Demers C , Gurfinkel E P , et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group . N Engl J Med . 1997 ; 337 : 447 – 452 .

30. Antman E M , McCabe C H , Gurfinkel E P , et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Qwave myocardial infarction: results of the Thrombolysis In Myocardial Infarction (TIMI) 11B trial . Circulation . 1999 ; 100 : 1593 – 1601 .

31. Ferguson J J , Califf R M , Antman E M , et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial . JAMA . 2004 ; 292 : 45 – 54 .

32. Antman E M , Morrow D A , McCabe C H , Murphy S A , Ruda M , Sadowski Z , et al. For the ExTRACT-TIMI25 Investigators. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction . N Engl J Med . 2006 ; 354 : 1477 – 1488 .

33. Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators . Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction . Lancet . 2001 ; 358 : 605 – 613 .

34. Gibson C M , Murphy S A , Montalescot G , Morrow D A , Ardissino D , Cohen M , et al. For the ExTRACT-TIMI 25 Investigators. Percutaneous coronary intervention in patients receiving enoxaparin or unfractionated heparin after fibrinolytic therapy for ST-segment elevation myocardial infarction in the ExTRACT-TIMI 25 trial . J Am Coll Cardiol . 2007 ; 49 : 2238 – 2246 .

35. Yusuf S , Mehta S R , Chrolavicius S , et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes . N Engl J Med . 2006 ; 354 : 1464 – 1476 .

36. Van de Werf F , Bax J , Betriu A , Blomstrom-Lundqvist C , Crea F , Falk V , et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology . Eur Heart J . 2008 ; 29 : 2909 – 2945 .

10


37. Antman E M , Hand M , Armstrong P W , Bates E R , Green L A , Halasyamani L K , et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction . Circulation . 2008 ; 117 : 296 – 329 .

38. Yusuf S , Mehta S R , Chrolavicius S , Afzal R , Pogue J , Granger C B . OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial . JAMA . 2006 ; 295 : 1519 – 1530 .

39. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators . Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes . Circulation . 1994 ; 90 : 1631 – 1637 .

40. The Direct Thrombin Inhibitor Trialists’ Collaborative Group . Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data . Lancet . 2002 ; 359 : 294 – 302 .

41. Di Nisio M , Middeldorp S , Büller H R . Direct thrombin inhibitors . N Engl J Med . 2005 ; 353 : 1028 – 1040 .

42. White H D , Aylward P E , Frey M J , et al. Randomized, double-blind comparison of Hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO) . Circulation . 1997 ; 96 : 2155 – 2161 .

43. Lincoff A M , Kleiman N S , Kereiakes D J , et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial . JAMA . 2004 ; 292 : 696 – 703 .

44. Stone G W , McLaurin B T , Cox D A , Bertrand M E , Lincoff A M , Moses J W . ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes . N Engl J Med . 2006 ; 355 : 2203 – 2216 .

45. Stone G W , White H D , Ohman E M , Bertrand M E , Lincoff A M , McLaurin B T . Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial investigators. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial . Lancet . 2007 ; 369 : 907 – 919 .

46. Steinberg D H , Shah P , Kinnaird T , Pinto Slottow T L , Roy P K , Okabe T . Bleeding risk and outcomes of bivalirudin versus glycoprotein IIb/IIIa inhibitors with targeted low-dose

unfractionated heparin in patients having percutaneous coronary intervention for either stable or unstable angina pectoris . Am J Cardiol . 2008 ; 102 : 160 – 164 .

47. Stone G W , Witzenbichler B , Guagliumi G , Peruga J Z , Brodie B R , Dudek D , et al. For the HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction . N Engl J Med . 2008 ; 358 : 2218 – 2230 .

48. Bittl J A , Strony J , Brinker J A , et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators . N Engl J Med . 1995 ; 333 : 764 – 769 .

49. Lincoff A , Bittl J , Harrington R , et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial . JAMA . 2003 ; 289 : 853 – 863 .

50. White H D , Ohman E M , Lincoff A M , Bertrand M E , Colombo A , McLaurin B T . Safety and efficacy of bivalirudin with and without glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes undergoing percutaneous coronary intervention: 1-year results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial . J Am Coll Cardiol . 2008 ; 52 : 807 – 814 .

51. Baetz B E , Spinler S A . Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases . Pharmacotherapy . 2008 ; 28 : 1354 – 1373 .

52. Connolly S J , Ezekowitz M D , Yusuf S , Eikelboom J , Oldgren J , Parekh A and RE-LY Steering Committee and Investigators , et al. Dabigatran versus warfarin in patients with atrial fibrillation . N Engl J Med . 2009 ; 361 : 1139 – 1151 .

53. Mega J L , Braunwald E , Mohanavelu S , Burton P , Poulter R , Misselwitz F , et al. ATLAS ACS-TIMI 46 study group. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial . Lancet . 2009 ; 374 : 29 – 38 .

54. Becker R C , Moliterno D J , Jennings L K , Pieper K S , Pei J , Niederman A and TRA-PCI Investigators . Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study . Lancet . 2009 ; 373 : 919 – 928 .

1

70 • Apical ballooning syndrome (tako-tsubo or stress-induced cardiomyopathy)

70 Apical ballooning syndrome (tako-tsubo or stress-induced cardiomyopathy)

Abhiram Prasad

Apical ballooning syndrome (ABS) is a distinct car-diac syndrome that was originally described in the Japanese population. 1,2 The term tako-tsubo (octopus trap) cardiomyopathy is used in Japan to describe the appearance of the left ventriculogram during systole that bears a resemblance to an octopus-trapping pot, which has a narrow neck and round bottom. ABS is also known as stress-induced or ampulla cardiomy-opathy. 3 The condition may be triggered by a stressful event, and the clinical presentation of ABS mimics a myocardial infarction. Thus, it is an important differen-tial diagnosis of acute coronary syndromes. 4

INCIDENCE AND DEMOGRAPHICS It has been estimated that ABS accounts for approxi-mately 1 – 2% of all patients presenting with an initial primary diagnosis of either an acute coronary syn-drome or myocardial infarction. 5 Approximately 90% of all reported cases of ABS have been in postmeno-pausal women. Less than 3% of the patients have been younger than 50 years. The fact that it occurs almost exclusively in postmenopausal women suggests that withdrawal from estrogens may contribute to the pathogenesis. It has been suggested that ABS may be under-diagnosed in males because of the higher preva-lence of coronary artery disease, but this is unlikely because of the consistent female predominance in all published studies.

PATHOPHYSIOLOGY Although the precise pathophysiology of ABS remains unknown, potential mechanisms include catechol-amine-induced myocardial stunning, and ischemia-mediated stunning due to multivessel epicardial or microvascular spasm. 6 Support for the catecholamine hypothesis is provided by the following observations: fi rst, many patients have an emotional or physical stressful trigger; secondly, a cardiomyopathy resem-bling ABS has been described in patients with pheo-chromocytoma and subarachnoid hemorrhage; thirdly, very high levels of catecholamines have been reported in some patients with ABS; and, fi nally, endomyocar-dial biopsies in these patients sometimes demonstrate contraction band necrosis, a feature of catecholamine

toxicity. 7 However, neither the elevation in circulating catecholamines nor the contraction band necrosis has proven to be a universal fi nding.

While epicardial spasm has been observed in some patients, it is not a common fi nding and hence it is un-likely to be the underlying cause of ABS in the vast majority of cases. In contrast, microvascular dysfunc-tion can be detected in at least two-thirds of the patients at the time of presentation and its severity correlates with the magnitude of troponin elevation and ECG abnormalities. However, it remains to be established whether the microvascular dysfunction is a primary pathophysiological mechanism or an epiphenomenon. Abnormal fatty acid or glucose metabolism has also been detected in these patients and the defect colocal-izes with the wall motion abnormality and takes longer to recover than the microvascular fl ow. 8

CLINICAL FEATURES A history of an emotional or physical stressful trigger that precipitates ABS can be elicited in approximately two-thirds of patients. Examples of common emotional triggers include the death of a family member, receiving bad news, severe argument, and public speaking. Exam-ples of physical triggers include non-cardiac surgery, severe illness, and experiencing severe pain. However, it is important to be aware of the fact that the absence of such a trigger does not exclude the diagnosis.

In general, the symptoms of ABS are similar to those of patients who have myocardial ischemia due to an acute coronary syndrome. 9 – 11 Approximately half of all patients present with angina-like chest pain at rest. Other common presenting symptom includes dyspnea, while syncope or out-of-hospital cardiac arrest is rare. Patients in intensive care units with a primary non-car-diac illness who subsequently develop ABS are more likely to have pulmonary edema, ischemic changes on the electrocardiogram, or elevated cardiac biomarkers as the presenting features. Mild to moderate conges-tive heart failure is frequent, but major hemodynamic decompensation is uncommon, and cardiogenic shock is a rare complication. Hypotension may develop due to the reduction in stroke volume, and in some cases due to dynamic left ventricular outfl ow tract obstruction. 12

2

SECTION 7 • ACUTE CORONARY PROBLEMS

DIAGNOSIS

There are no validated diagnostic criteria for ABS, but the proposed Mayo Clinic criteria do appear to be help-ful in making the diagnosis and can be applied at the time of presentation. All four criteria must be present ( Box 70.1 ). 13

In both of the above circumstances, the diagnosis of ABS should be made with caution, and a clear, stress-ful, precipitating trigger must be sought.

The typical patient is a postmenopaual woman pre-senting with symptoms of myocardial ischemia that is temporally related to a physical or emotional stress-ful event, with positive cardiac biomarkers and/or

an electrocardiogram that has evidence of ischemia. However, as a general rule, ABS should be consid-ered as a potential differential diagnosis of any patient with acute myocardial infarction. Another important population where ABS should be considered as a po-tential diagnosis is patients in intensive care units who develop an acute reduction in left ventricular systolic function in association with one or more of the follow-ing: pulmonary edema, hemodynamic compromise, ischemia or injury pattern on the electrocardiogram, or elevated biomarkers of myonecrosis.

Electrocardiogram There is considerable heterogeneity in electrocardio-graphic fi ndings. Approximately, one-third of patients have ST-segment elevation, mimicking a ST-elevation myocardial infarction. Typically, the elevation is present in the precordial leads, but it may be seen in the inferior or lateral leads. Alternatively, patients may also pres-ent with deep T-wave inversion or non-specifi c T-wave abnormality, and in some cases the electrocardiogram may be normal. The electrocardiogram is not helpful in distinguishing ABS from a ST-elevation myocardial infarction. 14 Characteristic evolutionary changes during the hospitalization include resolution of the ST-segment elevation, development of diffuse and often deep T-wave inversion that involves most leads, and prolongation of the corrected QT interval ( Figure 70.1 ). Transient patho-logical Q-waves may rarely develop. The time for the electrocardiographic abnormalities to resolve can be quite variable, but is usually 3 to 4 months.

Cardiac biomarkers Cardiac troponin is invariably elevated and peaks within 24 hours. In general, the magnitude of increase is less than that observed in patients with myocardial

BOX 70.1 PROPOSED MAYO CLINIC CRITERIA FOR APICAL BALLOONING SYNDROME. 13

1. Transient hypokinesis, akinesis or dyskinesis of the left ven-tricular midsegments with or without apical involvement. The regional wall motion abnormalities extend beyond a single epicardial vascular distribution. A stressful trigger is often but not always present.*

2. Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture. †

3. New electrocardiographic abnormalities (either ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin.

4. Absence of:†

– pheochromocytoma – myocarditis.

* There are rare exceptions to these criteria, such as those patients in whom the regional wall motion abnormality is limited to a single coronary territory. † It is possible that a patient with obstructive coronary atherosclerosis may also develop ABS. However, this is very rare in our experience, and in the published literature, perhaps because such cases are misdiagnosed as an acute coronary syndrome.

Section:

I aVR V1 V4

II

II

aVL V2 V5

III aVF V3 V6

Floor:

Figure 70.1 Diffuse T wave inversion and prolongation of the QT interval.

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infarction, and disproportionately low for the extent of left ventricular systolic dysfunction. Blood level of brain naturetic peptide (BNP), a marker of ventricular dysfunction, is generally elevated and correlates with the left ventricular end-diastolic pressure. 15

Coronary angiogram and left ventricular imaging Coronary angiography should be performed in a patient suspected of suffering with ABS in order to exclude an acute coronary syndrome. Patients with ABS either have mild atherosclerosis or angiographi-cally normal coronary arteries. Obstructive coronary artery disease may co-exist because of the advanced age of population.

The classical appearance and regional wall motion abnormality (mid- and apical segments) of the left ven-tricle are shown in Figure 70.2 . Basal function is gener-ally preserved and may even be hyperdynamic. The wall motion abnormality in nearly all cases extends beyond the distribution of any single coronary artery. The right ventricle also develops a similar pattern of regional wall motion abnormality in approximately one-third of cas-es. 16 Patients with combined left and right ventricular dysfunction tend to be sicker and more likely to develop congestive heart failure. In a signifi cant proportion of patients apical contraction is preserved, and the wall motion abnormality is restricted to the midsegments (apical sparing variant). 17 The so-called “inverted tako-tsubo” is a rare variant in which there is hypokinesis of the base of the heart with preserved apical function. Car-diac magnetic resonance is a useful imaging modality for documenting the extent of the regional wall motion abnormality, and differentiating ABS (characterized by the absence of delayed gadolinium hyperenhancement) from myocarditis and myocardial infarction in which delayed hyperenhancement is present. 18

TREATMENT

The initial management is generally directed toward treating myocardial ischemia since an acute coro-nary syndrome is the preliminary diagnosis in most cases. As a result, continuous ECG monitoring is initiated, and aspirin, intravenous heparin, and beta-blockers are administered. There are no evidence-based recommendations for the treatment of ABS as clinical studies have not been conducted in this novel cardiomyopathy. The strategy outlined is based on expert opinion. Supportive therapy leads to spontane-ous recovery in nearly all cases. Once the diagnosis has been made, aspirin can be discontinued unless there is co-existing coronary atherosclerosis. The effi -cacy of sympathetic blockade has not been formally tested. In the absence of contraindications, it is rea-sonable to empirically initiate a either a beta-blocker or a combined alpha- and beta-blocker because excess catecholamines have been implicated in the pathogenesis.

Initiation of angiotensin-converting enzyme inhibi-tor or angiotensin-receptor blocker therapy prior to discharge is reasonable. This is particularly impor-tant as the diagnosis may not be certain at the time of discharge and these drugs would be indicated for non-reversible left ventricular dysfunction. Inhibitors of the renin – angiotensin system can be discontinued once there is complete recovery of systolic function in ABS. Long-term beta-blocker or combined alpha/beta-blocker therapy should be considered with the aim of reducing the likelihood of a recurrent episode. Annual clinical follow-up is advisable because the natural his-tory of ABS remains unknown. The potential com-plications of ABS and their treatment are outlined in Table 70.1 .

Figure 70.2 Left ventriculogram in diastole and systole of a patient with apical ballooning syndrome illustrating preserved basal contraction, and akinesis of the mid- and apical segments.

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SECTION 7 • ACUTE CORONARY PROBLEMS

PROGNOSIS Ventricular dysfunction and the regional wall motion abnormalities are transient and resolve completely within a matter of days to weeks. In general, complete recovery occurs in virtually all patients by 4 – 8 weeks. The prognosis of ABS is good in the absence of sig-nifi cant underlying comorbid conditions. It is advis-able to assess the ejection fraction at 4 – 6 weeks after discharge from the hospital to document recovery of the cardiac function. In-hospital mortality from ABS has been estimated to be 1 – 2%. Long-term survival appears to be similar to that of the general age-matched population. In the subgroup of patients in whom there is a physical trigger, such as major surgery or illness, prognosis appears to be worse, most likely related to the underlying condition. The recurrence rate of ABS is approximately 10%. 19

References 1. Sato H , Tateishi H , Uchida T , et al. Tako-tsubo like left ventricular

dysfunction due to multivessel coronary spasm . In: Kodama K , Haze K , Hori M , eds. Clinical aspect of myocardial injury: from ischemia to heart failure [in Japanese] . Tokyo : Kagakuhyoronsha Publishing Co. , 1990 : 56 – 64 .

2. Tsuchihashi K , Ueshima K , Uchida T , et al. Angina pectoris-myocardial infarction investigations in Japan. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction . J Am Coll Cardiol . 2001 ; 38 : 11 – 18 .

3. Maron B J , Towbin J A , Thiene G , et al. American Heart Association contemporary definitions and classification of the cardiomyopathies: American Heart Association scientific statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention . Circulation . 2006 ; 113 : 1807 – 1816 .

4. Prasad A . Apical ballooning syndrome: an important differential diagnosis of acute myocardial infarction . Circulation . 2007 ; 115 ( 5 ) : e56 – e59 .

5. Bybee K A , Kara T , Prasad A , et al. Transient left ventricular apical ballooning syndrome: a mimic of ST-segment elevation myocardial infarction . Ann Intern Med . 2004 ; 141 : 858 – 865 .

6. Bybee K , Prasad A . Stress-related cardiomyopathy syndromes . Circulation . 2008 ; 118 : 397 – 409 .

7. Wittstein I S , Thiemann D R , Lima J A , et al. Neurohumoral features of myocardial stunning due to sudden emotional stress . N Engl J Med . 2005 ; 352 : 539 – 548 .

8. Kurisu S , Inoue I , Kawagoe T , et al. Myocardial perfusion and fatty acid metabolism in patients with tako-tsubo like left ventricular dysfunction . J Am Coll Cardiol . 2003 ; 41 : 743 – 748 .

9. Abe Y , Kondo M , Matsuoka R , Araki M , Dohyama K , Tanio H . Assessment of clinical features in transient left ventricular apical ballooning . J Am Coll Cardiol . 2003 ; 41 : 737 – 742 .

10. Desmet W J , Adriaenssens B F , Dens J A . Apical ballooning of the left ventricle: first series in white patients . Heart . 2003 ; 89 : 1027 – 1031 .

Table 70.1 Complications of apical ballooning syndrome.

Complication Comments Management

Congestive heart failure Occurs commonly. More often seen if there is co-existing right ventricular dysfunction.

Responds to diuretics. Rarely, severe respiratory failure develops due to pulmonary edema, and may require a short duration of intubation and mechanical ventilation.

Hypotension May be primarily due to left ventricular dysfunction or secondary to dynamic left ventricular outfl ow tract (LVOT) obstruc-tion. LVOT obstruction is an uncommon cause of hemodynamic instability, but should be investigated for using echo-cardiography in patients with signifi cant hypotension.

In the absence of heart failure, if LVOT obstruction is present, a cautious trial of intravenous fl uids and beta-blockers may reduce the obstruc-tion by decreasing the hypercontractility of the base of the left ventricle and increasing cardiac fi lling. Alternatively, an infusion of phenylephrine may be effective by raising the afterload and left ventricular cavity size in patients in whom beta-blockers or intravenous fl uids are contraindi-cated. Phenylephrine in this situation should be used with caution and close monitoring as there is the potential for a deleterious effect in the presence systolic dysfunction. Inotropes would be contraindicated in the presence of dynamic obstruction.

Cardiogenic shock Uncommon This is generally due to the systolic dysfunction of the left ventricle and is treated with standard therapies. Intraaortic balloon pump counter-pulsation is preferable. Inotropes may potentially be deleterious given the presumed role of catecholamines in precipitating ABS. However, if necessary, they may be used with close monitoring of the left ventricular function.

Mitral regurgitation 20 Dynamic outfl ow-tract obstruction may be associated with systolic anterior motion of the mitral leafl et and mitral regurgitation.

Recovery of left ventricular function is associated with resolution of the mitral regurgitation.

Arrhythmia Atrial and ventricular may occur but are uncommon. Serious ventricular tachycar-dia and fi brillation are rare.

Treatment of arrhythmias is as in any other situation. ICD therapy is not indicated for ventricular tachycardia or fi brillation as the cardiomyopathy is reversible.

Left ventricular thrombus 21 Anticoagulation should be considered during the initial presentation if severe left ventricular systolic dysfunction is present, and continued for a few weeks with warfarin if there is slow functional recovery in order to prevent thromboem-bolism.

Left ventricular thrombus may rarely be present during the acute phase and anticoagulation is clearly indicated in this circumstance.

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11. Gianni M , Dentali F , Grandi A M , et al. Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review . Eur Heart J . 2006 ; 27 : 1523 – 1529 .

12. Ohba Y , Takemoto M , Nakano M , et al. Takotsubo cardiomyopathy with left ventricular outflow tract obstruction . Int J Cardiol . 2006 ; 107 : 120 – 122 .

13. Prasad A , Lerman A , Rihal C S . Apical ballooning syndrome (tako-tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction . Am Heart J . 2008 ; 155 : 408 – 417 .

14. Bybee K , Motiei A , Syed I , et al. Electrocardiography cannot reliably differentiation of transient left ventricular apical ballooning syndrome from anterior ST-segment elevation myocardial infarction . J Electrocardiol . 2007 ; 40 : 38e1 – 38e6 .

15. Akashi Y J , Musha H , Nakazawa K , Miyake F . Plasma brain natriuretic peptide in takotsubo cardiomyopathy . QJM . 2004 ; 97 : 599 – 607 .

16. Elesber A , Prasad A , Bybee K A , et al. Transient cardiac apical ballooning syndrome: prevalence and clinical implications of right ventricular involvement . J Am Coll Cardiol . 2006 ; 47 : 1082 – 1083 .

17. Hurst R T , Askew J W , Reuss C S , et al. Transient midventricular ballooning syndrome: a new variant . J Am Coll Cardiol . 2006 ; 48 : 579 – 583 .

18. Sharkey S W , Lesser J R , Zenovich A G , et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States . Circulation . 2005 ; 111 : 472 – 479 .

19. Elesber A , Prasad A , Lennon R , et al. Four-year recurrence rate and prognosis of the apical ballooning syndrome . J Am Coll Cardiol . 2007 ; 50 : 448 – 452 .

20. Parodi G , Del Pace S , Salvadori C , et al. Tuscany Registry of Tako-Tsubo Cardiomyopathy. Left ventricular apical ballooning syndrome as a novel cause of acute mitral regurgitation . J Am Coll Cardiol . 2007 ; 50 : 647 – 649 .

21. Kimura K , Tanabe-Hayashi Y , Noma S , et al. Rapid formation of left ventricular giant thrombus with takotsubo cardiomyopathy . Circulation . 2007 ; 115 : e620 – e621 .

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