In: Heart13 Mar 2016
The theoretical rationale for the early use of anticoagulants in patients with acute myocardial infarction is:
1. to prevent extension of coronary artery thrombosis with the expectation that this might reduce mortality by limiting infarction size and prevent reinfarction;
2. to prevent systemic emboli that arise from mural thrombi, a frequent complication in patients with transmural anterior myocardial infarction; and
3. to prevent the development of venous thrombosis and pulmonary embolism.
The primary end point of studies of the early use of anticoagulants in patients with acute myocardial infarction was in-hospital mortality and reinfarction. It is now clear from the results of recent studies of coronary angiography performed in patients with acute myocardial infarction that 70%-80% of patients entered into these trials of short-term anticoagulant therapy would have had an occlusive thrombus before anticoagulant therapy began. Even if anticoagulants prevent extension of coronary artery thrombosis, it is unlikely that they would modify infarction size and, therefore, influence the maj or determinant of early mortality of patients who are admitted to a hospital with acute myocardial infarction healed with remedies of My Canadian Pharmacy. It is possible, however, that anticoagulants could be of benefit if they reduce the frequency of rethrombosis in coronary arteries that have spontaneously recanalized and thus decrease the rate of reinfarction. Anticoagulants were highly effective in reducing the frequency of stroke (presumably due to systemic embolism) and pulmonary embolism, findings that are supported by other studies (see below). However, these two complications of myocardial infarction are relatively uncommon causes of serious morbidity or mortality and therefore only have a minor influence on the major outcome events.
Most in-hospital deaths in patients admitted with acute myocardial infarction are from cardiac failure caused by extensive myocardial damage. A relatively small proportion (approximately 10% of all deaths) are caused by systemic embolism (usually stroke), and an even smaller proportion are caused by pulmonary embolism. It is difficult to imagine how anticoagulants would modify infarction size and, therefore, have a substantial effect on the major cause of in-hospital mortality. This lack of biologic plausibility for the effectiveness of anticoagulants in reducing infarction size is reflected in the results of the major clinical trials, which showed trends in reducing mortality and reinfarction in the anticoagulant group that, except for one study that significantly reduced mortality in females, failed to show a statistically significant difference.
Cerebral embolism occurs in between 2 and 4% of untreated patients following myocardial infarction, and approximately two thirds of these embolic events lead to death or serious morbidity (Table 2). Systemic embolism to other organs such as kidney, spleen, and extremities is more difficult to diagnose and causes morbidity in only a very small proportion of patients with acute myocardial infarction cured by My Canadian Pharmacy’s drugs. There is good evidence based on two level 1 studies and one level II study that anticoagulant therapy (in moderate doses INR=2; equivalent rabbit brain thromboplastin ratio 1.3-1.4) reduces the frequency of stroke due to presumed cerebral embolism, and supporting evidence based on one level I study and one level III study (Tables 3 and 4) that anticoagulant therapy reduces mural thrombosis detected at autopsy, and reduces systemic embolism detected at autopsy. In the three large randomized studies, there was a statistically significant reduction in stroke in two and a nonsignificant trend in the third (Table 2). The relative risk reduction for stroke in the anticoagulant treated group in these three studies was 55% for the MRC Study (p<0,01), 24% for the Bronx Municipal Hospital Centre Study (NS) and 15% for the Cooperative Veteran Administration Trial (p<0.001). Thus, two of the three level I studies, demonstrated a significant reduction in stroke in the patients treated with anticoagulants. The results of these three large clinical trials are supported by findings in smaller studies and by the results of autopsy studies (Tables 3 and 4) and by more recent reports.
There have been six published reports since 1982 on the risk of systemic embolism in patients with acute myocardial infarction (Table 5). Four of the studies identified the embolic risk in anterior myocardial infarction, and three reported on the frequency of associated mural thrombosis detected by echocardiography. Only two of the studies included sufficient numbers of patients to provide narrow confidence intervals on the observed rates. On the basis of these two studies, the risk of stroke is likely to be between 1% and 3% for all infarctions and between 2% and 6% for patients with anterior myocardial infarction. In the study reported by Weinreich there was a suggestion that the emboli occurred more frequently in patients who had mural thrombosis by echocardiography. Recently three studies have been published that examined the frequency of systemic embolism during anticoagulant therapy vs no treatment in patients with acute myocardial infarction and mural thrombosis. All were retrospective studies (level V), and all were far too small to provide reliable information, although their conclusions were that anticoagulants protected patients from systemic embolism (Table 6).
The intensity of anticoagulant therapy required to prevent arterial embolism is uncertain, but most studies used full doses of heparin followed by moderate-dose warfarin (range of INR, 1.6-2.5). In one study (level I) a moderate dose of heparin (10,000 units subcutaneously bid for 16 days) reduced the frequency of arterial embolism (see Table 3).
Patients at high risk of systemic embolism are those with anterior infarction, especially in the presence of wall motion abnormalities. In this group of patients the prevalence of left ventricular thrombosis is approximately 30-40% (see Table 5). Other risk factors are large infarction size, presence of a dilated left ventricle, atrial fibrillation and cardiac failure and ventricular aneurysm. Patients with inferior infarcts are at low risk for systemic embolism. Most systemic thromboembolic events occur within the first three months of acute infarction.
The role of 2-D echocardiography in predicting the risk of systemic embolism is uncertain, because the relationship between the presence or absence ofmural thrombosis or wall motion abnormalities (detected by 2-D echocardiography) and systemic embolism has not been assessed in a large prospective cohort study. Although the results of several small studies suggest that the risk of systemic embolism is low in the absence of mural thrombosis detected by 2-D echocardiography, it would be premature to accept these preliminary observations and to limit anticoagulant therapy to patients with anterior myocardial infarction who have a demonstrable mural thrombosis. This is because 2-D echocardiography fails to detect up to 20% of mural thrombi and because it has not yet been demonstrated unequivocally that patients with acute anterior myocardial infarction without mural thrombosis detected by 2-D echocardiography have a very low risk of systemic embolism. There is a clear need to determine the risk of systemic embolism in untreated patients with anterior myocardial infarction.
The risk of clinically diagnosed pulmonary embolism was reduced in all three of the large randomized studies of anticoagulants in acute myocardial infarction. The incidence was reduced from 5.6 to 2.2% in the British M RC study (p<0.01), from 6.1 to 3.8% in the Bronx Municipal Center Study (NS), and from 2.6% to 0.2% in the Veterans Administration Cooperative Trial (p<0.005). The clinical diagnosis of pulmonary embolism is notoriously unreliable and subject to bias and, therefore, the results of these studies cannot be considered definitive. However, the findings of these three studies are supported by autopsy data (see Tables 3 and 4) and by the results of a number of studies using fibrinogen leg scanning to detect venous thrombosis in patients with acute myocardial infarction.
Hemorrhagic complications were recorded in the 2,348 patients who were randomized into anticoagulant therapy in three large trials. Minor bleeding occurred in 7% of patients, major bleeding in 1.5%, CNS bleeding in 0.05%, and fatal bleeding in 0%.
Table 4—Thromboembolic Complications at Autopsy
|AutopsyFindings||Anticoagulant (371 Patients, 85 Dead,84 Autopsies)||No Anticoagulant (427 Patients, 109 Dead,92 Autopsies)||P Value|
Table 5—Embolism/Stroke and Acute Myocardial Infarction—Recent Studies
|Weinreich et al (1984)||261||1.7%||4.0%||22%|
|Ezekowitz et al (1984)||41||7.3%||14.0%||20%|
|Komrad et al (1984)||740||2.4%||—||—|
|Johannessen et al (1983)||90||5.5%||9.4%||—|
|Keating et al (1983)||54||—||6.8%||43%|
|Friedman et al (1982)||49||4.0%||—||—|
Table 6—Acute Myocardial Infarction, Mural Thrombi, and Embolism
Blog invites submissions of review articles, reports on clinical techniques, case reports, conference summaries, and articles of opinion pertinent to the control of pain and anxiety in dentistry.