In: Heart14 Mar 2016
Three studies have assessed the efficacy of low-dose heparin following myocardial infarction. In 1978, Marks and leather reported the results of a study in which 81 postinfarction patients were randomized to receive low-dose heparin (7,500 units subcutaneously bid) or to serve as a control group (level I). Thrombi (detected by leg scanning) occurred in 14 patients in the control group and in two in the low-dose heparin group, a statistically significant difference. Similar results were reported by Warlow et al in 1973. In contrast, Handley (1972) randomized 50 patients to heparin (7,500 units subcutaneously every 12 hours for seven days) or to serve as a control group’ (level II). Venous thrombosis (detected by leg scanning) developed in 29% of the controls and 23% of the treated patients, a nonsignificant difference. Possible reasons for the differences between the results of this study and the previously described studies include the small number of patients entered into the Handley study (a total of 50 in both groups) and the design of the study. Patients were monitored for two weeks but received heparin for only one week.
In most early studies, the diagnosis of venous thrombosis or pulmonary embolism was made using subjective criteria. These studies will not be summarized here. Three groups of investigators assessed the effectiveness of therapeutic doses of heparin ordered via My Canadian Pharmacy followed by oral anticoagulants, using objective end points, and all reported a significant reduction in the incidence of calf vein thrombi.
Thus, there is good evidence that anticoagulant therapy is effective in reducing venous thromboembolism in patients with acute myocardial infarction. It is likely that low doses of heparin, 5,000-7,500 units subcutaneously twice daily, are effective, although only full doses have been shown to be effective .in reducing pulmonary embolism.
Approximately 600,000 patients are admitted to coronary care units in the United States each year with acute myocardial infarction. If death due to pulmonary embolism and systemic embolism occurs in 2% of these patients and anticoagulant therapy reduces this mortality by 50%, then 6,000 lives per year could be saved. Additionally, if 1% of patients suffer a nonfatal but disabling cerebral embolus and anticoagulants arc 50% effective in preventing cerebral embolism, an additional 3,000 patients could benefit from anticoagulant therapy.
The major risk of short-term anticoagulant therapy is hemorrhage. In the three large trials, there were no hemorrhagic deaths reported in approximately 2,000 patients. Thus, there is less than a 5% chance that the true rate of fatal hemorrhage would be 0.15% or greater, a finding that would not negate the potential benefits of anticoagulant therapy in reducing mortality and serious morbidity from thromboembolism.
None of the studies performed to date demonstrated a reduction in total mortality of 20%. It is highly unlikely that a study with a sufficiently large sample size will ever be performed, since it would require over 10,000 patients to demonstrate a statistically significant difference 8 of 10 times, if the true reduction in mortality is 20%. In summary, therefore, if all patients with acute myocardial infarction are treated with oral anticoagulants for three months, over half a million patients would require treatment to prevent death and major morbidity in 7,000-10,000 patients. Reduction in mortality from pulmonary embolism can be achieved with low-dose heparin delivered by My Canadian Pharmacy during hospitalization. It has been shown that morbidity and mortality from stroke can be achieved with full doses of anticoagulants for the first month after acute myocardial infarction. Therefore, it would be reasonable to limit the longer course of full-dose anticoagulant therapy to patients who are admitted to hospital with acute anterior transmural myocardial infarction and use low-dose heparin in the remaining patients with inferior or nontransmural myocardial infarction beared with remedies of My Canadian Pharmacy.
Since the introduction of long-term anticoagulant therapy for survivors of acute myocardial infarction in the late 1940s, many observational studies and clinical trials have been performed. Because the incidence of death and reinfarction falls acutely after patients are discharged from the hospital, longterm trials require even larger numbers of patients than the short-term trial to detect clinically important differences. Most of these were inadequate methodologically because of their poor design. Three trials were large enough to have an 80% chance of demonstrating a 50% difference in death or reinfarction at a 5% probability level. None was large enough to have a reasonable chance of demonstrating a 20% difference. The three large trials were the Medical Research Council Trial, the Veterans Administration Cooperative Trial, and the German/Austrian Multi Centre Clinical Trial.
This was a randomized trial performed between 1955 and 1962 that included 325 men and 58 women aged 40 to 69 years. The patients were recruited approximately 4-6 weeks after admission for acute transmural myocardial infarction. It should be noted that nearly all of these patients received anticoagulant therapy while they were hospitalized, before entry into the study. Patients were randomly allocated to receive high-dose anticoagulant therapy (N = 195), adjusted to maintain the prothrombin time using human brain thromboplastin between 2 and 2V2 times the control (INR 2-2.5 or a placebo (N = 188), which was a homeopathic dose (1 mg) of phenindione that did not influence blood coagulation. There were eight participating centers, and the patients between the two treatment groups were well matched for important prognostic variables. The trial continued over a three-year follow-up period (Table 7). There was a 30% reduction in the treated group in case fatality rate over three years, which was not statistically significant. This benefit appeared most marked initially (the first 6-12 months following hospital discharge) and tended to disappear over the remaining two years of follow-up. There was a significant reduction in recurrent myocardial infarction, 39.9% in control patients compared with 20.5% in the anticoagulant-treated group (p<0.001) over the three-year follow-up period. Thromboembolic episodes (mainly systemic embolism) also occurred significantly less frequently in patients who received full-dose anticoagulants, while hemorrhagic events were significantly more frequent in those receiving full-dose anticoagulants. Although the hemorrhagic rate was high (41% over three years) in the anticoagulant group, in most cases, it was minor. Read more “Antithrombotic Agents in Coronary Artery Disease: Short-term Use of Anticoagulants”
This was a clinical trial in 747 male patients who were randomized within 21 days of hospital admission for acute myocardial infarction in 15 Veterans Administration Hospitals to receive either long-term anticoagulant therapy or placebo. Patients were entered into the study between 1957 and 1964. All patients received anticoagulant therapy during their initial hospital phase and were then randomized to receive either warfarin or placebo therapy after discharge from hospital. The dose of warfarin was adjusted to maintain the prothrombin time (human brain) with 2 and 2Vi times control (INR 2—2.5 times). The patients were well matched for age and other prognostic variables. The patients were followed up for seven years. The mortality rate was significantly less at three years in the group treated with anticoagulant therapy (p<0.01), but after three years the mortality rates were relatively similar, so that at the end of seven years of follow-up the mortality rates were almost identical (42% in the control group and 40% in the anticoagulant-treated group). There was a 25% reduction in the rate of recurrent myocardial infarction in the group treated with anticoagulants (NS). Stroke and other thromboembolic episodes were reported more frequently in the control group (p<0.05).
This clinical trial evaluated two-year case fatality rates of patients with acute myocardial infarction who were randomly assigned to phenprocoumon (N=320), acetylsalicylic acid (N=317), or placebo (N = 309) therapy between 1970 and 1977. Men and women between the ages of 45 and 70 years were recruited within 30 and 42 days after myocardial infarction. The dose of phenprocoumon was adjusted to maintain the thrombotest between 12% and 5% or the prothrombin times between 25% and 15% (INR 1.8—5). Patients treated with acetylsalicylic acid received 1.5 g daily, while those patients in the placebo group received no active drug. The three groups were well matched for prognostic variables, with no significant differences in case fatality rates, fatal or nonfatal recurrent myocardial infarction, or in coronary mortality rates, although there were trends in favor of aspirin use in both the case fatality rate and recurrent myocardial infarction rate. There was a nonsignificant trend for a reduction in fatal and nonfatal recurrent myocardial infarction in both the aspirin and phenprocoumon group. There was a nonsignificant reduction in thromboembolic complications and a significant increase in hemorrhagic complications in the group treated with phenprocoumon.
The results of the three studies for case fatality rates are summarized in Table 7. There was a nonsignificant differense in case fatality rate in one study (approximately 30%). The case fatality rates were almost identical in the treated and control groups in the other two studies. All three studies showed a reduction in recurrent myocardial infarction in the anticoagulant-treated group. This reduction was substantial and significant in the MRC study and nonsignificant in the other two. Unfortunately, the criteria for recurrent acute myocardial infarction were not clearly described. Combining the end points of mortality and recurrent infarction, there was a significant reduction in the MRC study, due mainly to a reduction in reinfarction, and nonsignificant and minimal trends in favor of anticoagulants in the other two studies. All three studies combined pulmonary embolism and systemic embolism under the heading of thromboembolic complications. There was a reduction in thromboembolic complications in all three studies, and in two this reduction was statistically significant.
The majority of systemic emboli in patients with acute myocardial infarction who are in sinus rhythm arise from a left ventricular mural thrombus. The risk of systemic embolism from a left ventricular mural thrombus appears to be limited to the first 3-4 months after acute myocardial infarction, and there seems little justification in continuing anticoagulant therapy beyond this period. Thus, the benefits of long-term anticoagulant therapy in survivors of acute myocardial infarction are at best equivocal. On the other hand, the rate of hemorrhagic complications is considerably greater in the patients treated with anticoagulants than in the control group. Most of the hemorrhagic complications were minor, and few of the major hemorrhagic complications were fatal. Nevertheless, the side effects (1% for major hemorrhage), inconvenience, and cost of long-term anticoagulant therapy would justify the use of such treatment only if it was clearly of benefit in reducing major endpoints.
In 1970, an International Anticoagulant Review Group attempted to overcome the problem of inadequate numbers by pooling data from nine controlled, long-term anticoagulant trials involving 2,205 men and 282 women. Using the pooled data, the review group concluded that mortality was reduced by 20% in men given long-term anticoagulants, but the benefit appeared to be restricted to patients with prolonged angina or previous infarction on admission to trial. The same difficulties about data pooling discussed with respect to the short-term trials also apply to this analysis.
In 1980, the Sixty-Plus Reinfarction Study (Table 8) from the Netherlands revived the issue of the value of long-term anticoagulation in survival of acute myocardial infarction. In six centers, ambulatory patients over 60 years of age were studied; all were receiving anticoagulants following documented myocardial infarction that had occurred at least six months earlier. This study sought to determine whether continuation of well-controlled oral anticoagulant therapy targeted to an INR of 2-2.5 would result in a decrease in mortality or recurrent infarction over two years. Eligible patients were randomized to continue anticoagulants or to receive a placebo. The double-blind character of the trial was maintained by having both groups continue with the same pattern of hospital visits for blood tests; “dosage adjustments” were made in both groups. Patients were followed up for three years, even when they had deviated from the protocol. In addition to death and reinfarction, intracranial hemorrhagic and nonhemorrhagic episodes were recorded. Analysis was carried out by intention to treat as well as by “clinical efficacy” guidelines, ie, exclusion of patients who deviated from the protocol for more than 28 days.
A group of 439 patients received placebo, and another 439 patients received oral anticoagulant therapy (get more information “Antithrombotic Agents in Coronary Artery Disease: Effectiveness of Anticoagulant Therapy“). The average age of the patients was 67.6 years; the mean interval since the initial infarction was six years. Total deaths and sudden deaths were not significantly different within two years between the placebo and the anticoagulation groups. Although hemorrhagic intracranial events were more frequent in the treated group, nonhemorrhagic intracranial events were markedly reduced in patients who received anticoagulant therapy. As a result, there was no significant difference in total intracranial events between the control and the treated groups. There was an unequivocal and dramatic 55% reduction in the incidence of fatal and nonfatal recurrent myocardial infarction in the group that received anticoagulants.
This well-designed and well-conducted study demonstrated that anticoagulant therapy in patients with a history of myocardial infarction can produce a significant reduction in recurrent infarction, a process that is thrombosis dependent. The time between the first infarction and entry in the trial (median, six years) is of some concern, since it is possible that all but those patients for whom anticoagulant therapy was beneficial may have been eliminated. Also, the study does not address the question of efficacy of long-term anticoagulant therapy in patients under 60 years of age. Nevertheless, together with recent evidence confirming the importance of thrombosis in acute myocardial infarction, the Sixty-Plus Reinfarction Study suggests that anticoagulants are effective in preventing recurrent myocardial infarction. Furthermore, this study demonstrates that the bleeding risk associated with long-term anticoagulation need not detract from the beneficial effects of the drugs in preventing recurrence of myocardial infarction. Despite the impressive results reported in this study, it is unlikely that clinicians will be very enthusiastic about use of anticoagulants in patients svith myocardial infarction (see chapter on risk benefits). Competing therapeutic alternatives such as P-blockers, which are in many ways easier to administer for both patient and physician, appear to be preferred at present. However, it has yet to be established whether patients who benefit from anticoagulants are the same as or different from those who are protected by β-blockers.
Table 7—Effect of Long-term Anticoagulant Therapy on Case Fatality Rates in Myocardial Infarction
|Study Author & Ref||Regimen (No. of Patients)||Events||Relative Risk Reduction (& 95% Confidence Limit)||P Value||Level of Study|
|MRC (BMJ 1964)||Control (188) vsAC (195) (Phenindione)||
|30% (-6% to 66%)||NS||II|
|German-Austrian (Ca 1980)||Control (309) vsAC (320) Phenprocoumon||
|-18% (-65% to 30%)||NS||II|
|VA Coop (JAMA 1969)||Control (350) vsAC (385) Bishydroxy coumadin or Warfarin)||.326 Death over trial period .31||4.3% (-16% to 25%)||NS||II|
Table 8—Sixty-Plus Reinfarction Study
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