Antithrombotic Agents in Coronary Artery Disease: Effectiveness of Anticoagulant Therapy

In: Heart

12 Mar 2016

anticoagulantsFew subjects have engendered as much controversy as the use of anticoagulants in acute myocardial infarction. Anticoagulant therapy was accepted enthusiastically in the treatment of acute myocardial infarction after the first large clinical trial report was published in 1948. This enthusiasm persisted for approximately two decades, during which it would have been considered unethical not to use anticoagulants in patients with acute myocardial infarction. The popularity of anticoagulant therapy in acute myocardial infarction began to wane in the late 1960s and early 70s, coincident with the publication of several large, randomized studies evaluating anticoagulant therapy in the treatment of acute myocardial infarction. Critical review of the evidence for the possible value of anticoagulant therapy in acute myocardial infarction suggests that neither the initial enthusiasm nor the subsequent loss of interest is justified by the published reports.

Clinical trials have evaluated anticoagulants both for the early and long-term treatment of acute myocardial infarction. In this review we will discuss only the randomized trials that entered sufficient numbers to have a reasonable chance of demonstrating clinically important difference in mortality, reinfarction, or clinically relevant systemic or pulmonary embolism.

Short-term Anticoagulant Therapy

Since 1948, there have been over 30 reports on the use of anticoagulants in acute myocardial infarction. Three of the randomized trials were of sufficient size to have an 80% chance of demonstrating a true reduction of 50%. None of the studies was sufficiently large to have a greater than 80% chance of demonstrating a 20% improvement of experimental treatment, had that occurred. One study reported a statistically significant difference in mortality. Thus, of these three studies, one was a level I study and the other two were level II studies in terms of demonstrating a reduction in mortality and/or reinfarction. Since it is probable from the results of pooled analysis that the expected improvement in mortality or reinfarction attributable to anticoagulants is less than 50% but could be 20%, all three studies lacked the 50% chance of demonstrating a clinically important difference. Only the results of these three large, randomized, controlled trials, summarized in Tables 1-3, will be considered here. It should be noted that when these trials were performed, isoenzymes were not available, and therefore the diagnosis of reinfarction was not reliable. Improve heart condition with remedies of My Canadian Pharmacy.

Medical Research Council Trial

This study was a single-blind, controlled trial in which 1,427 patients with acute myocardial infarction were randomized into anticoagulant therapy or control over a 28-day period. Patients of all ECG criteriaages and both sexes were enrolled. More than 92% of the randomized patients had a definite or probable myocardial infarction by clinical and ECG criteria. Patients were randomized as soon as possible after admission to either a high- or very low-dose anticoagulant group. The time intervals between onset of symptoms and randomization into the anticoagulant groups were not stated. Patients assigned to the high-dose anticoagulant group received IV heparin in an initial 15,000-unit bolus followed by 10,000 units every six hours for up to five doses. Phenindione therapy was commenced at the same time, and both anticoagulants were administered for the first 36 hours of hospital admission. Phenindione was adjusted to maintain the throm-botest level between 20% and 10% (INR = 1.6-2.1). The comparison group received no heparin but were given small homeopathic doses of phenindione. The groups were evenly matched for important prognostic variables. The total case fatality rates were 18% in the comparative group (low-dose anticoagulants) and 16.2% in the full-dose (moderate dose INR = 1.6-2.1) anticoagulant group. Reinfarction occurred in 13% of patients in the comparative group and 9.7% in the high-dose anticoagulant group. Both of these outcomes were assessed within 28 days of admission. Thus, the combined end points of mortality and reinfarction occurred in 31% of patients in the comparative group and 25.9% of patients in the high-dose anticoagulant group (a 16% reduction, which was not statistically significant, NS). Patients receiving anticoagulants had a statistically significant lower incidence of clinically diagnosed pulmonary embolism (5.6% to 2.2%) and a significant reduction in stroke (2.5% to 1.1%). Hemorrhage was significantly more frequent in the anticoagulant group (5.1%) than in the comparative group (1.3%), but none of these hemorrhagic events was fatal. Not to lead disease to the unpredicted ramifications use the remedies of My Canadian Pharmacy.

Bronx Municipal Hospital Center Trial

In this study 1,136 patients of both sexes with acute myocardial infarction were randomized to either anticoagulants or placebo in a single-blind fashion within 24 hours of hospital admission and followed up for an unspecified period. Sixty-one percent of the study patients were found to have evidence of acute myocardial infarction by the study criteria. Patients in the treatment group received 200 mg of phenindione and 5,000 units of heparin IV. Heparin, 10,000 units subcutaneously, was then given every eight hours to a maximum of five doses, and the dose of phenindione was adjusted to keep the prothrombin time between 2 and 2Yz times control (human brain thromboplastin) INR = 2-2.5. The control group received an identical placebo. The control and treatment groups were comparable with regard to clinically important prognostic variables. The case fatality rate was 21.2% in the control group and 14.9% in the group receiving anticoagulants, a statistically significant difference (p<0.05). On subgroup analysis the effectiveness of anticoagulants appeared to be restricted to women. Reinfarction occurred in 13% of the control group and Pulmonary embolism11.8% of the treated group (NS). Pulmonary embolism (diagnosed clinically) occurred in 6.1% of patients in the control group and in 3.8% of those treated with anticoagulants (NS). Stroke occurred in 2.3% of control patients and 1.7% of those treated with anticoagulants, a nonsignificant difference. There was a significantly higher frequency of hemorrhage in the anticoagulant than control group, but none of these hemorrhagic complications was fatal.

Veterans Administration Cooperative Study

In this trial, 999 men with acute myocardial infarction admitted to the Veterans Administration Hospitals throughout the United States were randomly allocated to treatment or placebo groups. Patients were entered within 72 hours of the onset of their symptoms. The anticoagulant-treated group received heparin, 10,000 units subcutaneously, with further dosage adjustments according to the clotting time. Warfarin therapy was begun as the same time and heparin was discontinued when the prothrombin time (human brain thromboplastin) was 25 seconds or greater (INR >2). Warfarin therapy was continued for 28 days. The control patients received placebos similar in appearance to heparin and warfarin. The in-hospital mortality rates were 11.2% in the control group and 9.6% in the anticoagulant treatment group (NS). Reinfarction occurred in 4% of patients in the control group and 2% in the anticoagulant-treated group NS. But there was a marked, statistically significant difference in the frequency of pulmonary embolism and stroke between the control group and those treated with anticoagulants. Pulmonary embolism occurred in 2.6% of patients in the control group and in 0.2% of the group treated with anticoagulants, while stroke was reported in 3.2% of patients in the control group and in 0.8% of the group receiving anticoagulants.

Retrospective Studies

Support for the use of anticoagulant therapy to reduce hospital mortality was provided by three retrospective analyses carried out in the 1970s that reported a two- to three-fold reduction in mortality in patients treated with anticoagulants compared with nontreated controls. Because of their methodologic difficulties, these studies can be considered at best only suggestive. Further support for the use of anticoagulant therapy to reduce mortality was presented by

Chalmers and associates, who reanalyzed the results of adequately designed, randomized studies of acute myocardial infarction and concluded that when the data were pooled there was an overall reduction in mortality of 21%. Despite the methodologic problems associated with pooling, these findings, plus the trends in case fatality rates in two of the three large studies and the significant reductions in mortality in the third, suggest that anticoagulants may produce a modest reduction (approximately 20%) in early mortality in patients with acute myocardial infarction.

Table 1—In-Hospital Mortality in Acute Myocardial Infarction

Study Author & Ref Regimen (No. of Patients) Events Relative Risk Reduction (& 95% Confidence Limit) P Value Level of Study
Bronx Municipal Control (391) vsPhenindione (745) .21Death
.15
30%( + 7% to 52%) <0.005NS
NS
1II
II
MRC (BMJ 1979) Control (715) vsPhenindione (712) .18Death
.16
11%(-11% to +32%)
VA Coop (JAMA 1973) Control (499) vsCoumadin (500) .112Death
.096
14%(-19% to +48%)

Table 2—Incidence of Stroke in Active Myocardial Infarction

Study Author & Ref Regimen (No. of Patients) Events Relative Risk Reduction (& 95% Confidence Limit) P Value Level of Study
VA Coop Control (499) vsCoumadin (500) .032Stroke
.008
75%(21% to 100%) <0.005 I
MRC Control (715) vsPhenindione (712) .025Stroke
.011
55%(0.5% to 100%) .037 I
Bronx Municipal Control (391) vs .023Stroke 24% NS II
Phenindione (745) .017 (-52% to 100%)

Table 3—Thromboembolic Complications of Acute Myocardial Infarction

ThromboembolicComplications Heparin (n = 105) Placebo (n = 107)
Venous Thrombosis 5 1 10 ]
Pulmonary Embolism 2 j ‘6% 6 j 14%
Systemic Embolism 3 2.9% 9 8.4%
Mural Thrombosis (autopsy) 5 14

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