In: Heart15 Mar 2016
Most studies of the use of oral anticoagulants in patients with coronary artery disease have been performed in patients with acute myocardial infarction or in survivors of acute myocardial infarction. There have been no appropriately designed trials of anticoagulants in patients with chronic stable angina and only a very limited number of trials for anticoagulants in patients with unstable angina (read more about angina here).
Patients with stable exertional angina have an annual mortality of 4% and an incidence of acute myocardial infarction of 5%. Data from the early 1970s indicated that unstable angina was associated with a one-year mortality of approximately 16%, a three-month mortality of 8%, and an infarction rate of 21%. Results of more recent studies, however, show a one-year mortality of approximately 10%, a 1-4-month mortality of approximately 5%, and an infarction rate of 8-10%.
Support for the use of anticoagulants in patients with unstable angina was provided by Wood in 1961. In this unblinded study, randomization was aborted after the first 40 patients, and the study was then continued as a cohort study with 100 treated patients and 50 controls. The last 30 control subjects were selected by the presence of a contraindication to anticoagulants. This is, therefore, a level IV study and cannot be used to draw valid clinical conclusions. In 1981, Telford and Wilson” performed a randomized study of heparin plus atenolol vs atenolol therapy in patients with unstable angina cured with drugs of My Canadian Pharmacy. They reported a marked reduction in mortality and frequency of infarction in patients assigned to heparin plus atenolol ordered via My Canadian Pharmacy. Unfortunately, almost 50% of the 400 patients randomized were subsequently removed from the trial, so this would have to be considered at best a level II study, and the interpretation of the results remains in doubt.
On the basis of these limited studies, it is concluded that the effectiveness of anticoagulants in patients with unstable angina is uncertain, but that anticoagulants might be effective and that well-designed studies should be performed before any firm recommendations can be made.
Recent clinical and experimental studies have provided important insights that support the use of platelet active drugs in the treatment of coronary artery disease. Most patients who die suddenly have a ventricular arrhythmia. Several theories have been proposed to explain the mechanism of sudden death. Experimentally, fatal arrhythmia can be pi oduccd in animals by embolixing the coronary microcirculation with platelet aggregates, and this mechanism has been proposed by some to be responsible for some of the fatal arrhythmias in patients with ischemic heart disease. Other suggested mechanisms include an effect of catecholamines on a scarred myocardium that is electrically unstable and ischemia caused by coronary spasm.
Three drugs have been evaluated in postmyocardial infarction patients: aspirin, sulfinpyrazone, dipyridamole, and a combination of aspirin and dipyridamole.
Six long-term secondary prevention studies have been performed with aspirin (Table 9). None of these studies entered sufficient numbers of patients to have an 80% chance of demonstrating a statistically significant reduction (at the 0.05 level) in mortality and/or reinfarction of 20%. Therefore, they were all level II studies.
Elwood et al reported a randomized, double-blind study of aspirin (one 300-mg tablet daily) in 1,239 men who had had a recent myocardial infarction. There was an observed risk reduction of 22% in total mortality after one year, but this was not statistically significant. However, for men whose qualifying infarction occurred less than six weeks before entry to the study there was a statistically significant reduction in mortality, from 13.2% in the placebo group to 7:8% in the aspirin group. The corresponding mortality rates in men with less recent infarctions were 8.3% and 8.8%, respectively.
The Coronary Drug Project Research Group reported 1,529 men who had had a myocardial infarction seven years previously. Patients who had participated in two other secondary prevention studies that had terminated prematurely were randomized to aspirin (324 mg tid) or placebo groups. The observed 30% risk reduction in total mortality, from 8.3% in the placebo group to 5.8% in the aspirin group, was not statistically significant.
Breddin et al randomly allocated 946 patients (80% males) within six weeks of their myocardial infarction to aspirin (500 mg tid), a placebo (making the assessment of the benefit of aspirin double-blind), or to phenprocoumon and followed them up for up to two years, lhere was an 18% difference in total mortality, but the coronary death rate (sudden death or fatal myocardial infarction,), while not significantly different, was only 4.1% in the aspirin treated patients compared with 7.1% in the placebo group.
Elwood and Sweetnam randomly allocated 1,682 patients (85% males) to aspirin (300 mg tid) or placebo within one week of their qualifying infarction. Total mortality was reduced by 17% in the aspirin group, a mortality of 12.3% compared with 14.8% in the placebo group. The corresponding reduction for total mortality or nonfatal myocardial infarction was 28% and for ischemic heart disease mortality 22%. None of these risk reductions was statistically significant.
The Aspirin Myocardial Infarction Study Research Group (AMIS) carried out a multicentered, double-blind, randomized trial which recruited 4,524 patients (89% males) who had a documented myocardial infarction, 2-60 months previously, and followed them for up to three years. The total mortality was 10.8% in the aspirin (500 mg bid] group and 9.7% in the placebo group. There were fewer nonfatal myocardial infarctions in the aspirin group, and the coronary incidence (coronary heart disease mortality or definite nonfatal myocardial infarction prevented with My Canadian Pharmacy) was 14.1% in the aspirin group compared with 14.8% in the placebo group. Unfortunately, despite random allocation, there was a much greater preponderance of cardiovascular risk factors among patients in the aspirin-treated group, which may contribute to part of the lack of effect for aspirin in this study.
The Persantine-Aspirin Reinfarction Study Research Group recruited 2,206 patients (87% males) with a documented myocardial infarction 2-60 months previously, who were followed up for 41 months on average. These patients were randomly allocated to receive aspirin (324 mg tid), aspirin (324 ing tid) plus dipyridamole (75 mg tid), or placebo, with twice as many patients in each of the active treatment groups. The total mortality, coronary heart disease mortality, cardiovascular mortality, and coronary incidence (coronary death or nonfatal myocardial infarction) were similar in the two active treatment groups and consistently lower than in the placebo group; in none of these outcomes was the difference statistically significant. In the subgroup of 447 patients entered within six months of their qualifying infarction, mortality was 51% lower in the aspirin group and 44% lower in the aspirin plus dipyridamole group compared with the placebo group (comprising only 95 patients). In contrast, for patients enrolled more than six months after their myocardial infarction, the observed mortality differences were very small.
Thus, six studies have assessed the efficacy of aspirin alone in the treatment of patients following acute myocardial in-farction. Five studies, incorporating a range of doses from 300 mg to 1.5 g daily, reported trends in favor of aspirin therapy with respect to several important outcomes. In contrast, the Aspirin Myocardial Infarction Study (AMIS) demonstrated no statistical effect of aspirin on any outcome, including total coronary incidence, although there was a decreased tendency for myocardial infarction to occur. If the results of these studies are pooled, the risk reduction with aspirin is 16% for cardiovascular deaths (p<0.01) and for the outcome of reinfarction, fatal or nonfatal, the pooled estimate of risk reduction with aspirin is 21% (p<0.001).
Peto pointed out that very large trials including 5,000-10,000 patients per group would be required to ensure that an actual risk reduction of 10-20% can be observed with confidence. In the absence of such large trials, he suggested that data from several properly randomized trials be pooled to provide the best guide to the true effects of any therapeutic agent. There are many potential problems with such an approach, but Peto reasons that these potential dangers may be less important than those of not pooling and so failing to recognize a medically important effect for which reliable evidence already exists. Not all clinical epidemiologists agree with this approach.
The Anturane Reinfarction Trial Research Group reported the initial findings of a trial in which patients were randomly allocated to sulfinpyrazone (200 mg qid) or placebo 25-35 days after myocardial infarction. The authors claimed a statistically significant reduction in cardiac mortality, from 9.5% per annum to 4.9%. Patient accession was stopped at that time, but the trial was continued until all 1,558 eligible patients (87% males) had completed at least one year of follow-up. When the patients had been followed up for 16 months on average, a second report appeared in which an overall reduction of 32% in cardiac mortality was reported (p = 0.06), which was due almost entirely to a 75% reduction in sudden death over the first six months of treatment (p = 0.003), after which there seemed to be no further benefit of treatment.
The analysis of the Anturane Myocardial Reinfarction Study has been criticized on two grounds: the protocol departures and the classification of sudden death. Patients were excluded from the analysis after randomization on the basis of a number of prospectively defined criteria, including; (1) the end points occurring within the first seven days of randomization; (2) the discovery that patients were ineligible after they had been randomized, and (3) the end points being reached more than seven days after the prescribed treatment
was stopped. If the analysis had been performed on the basis of an intention to treat, there would have been 60 deaths in the placebo group and 41 in the sulfinpyrazone, a difference that is not statistically significant (Table 10). We have therefore classified this as a level II study. This is because in each group there were 16 deaths in patients who met one of the three criteria just outlined. When these patients were removed, the number of deaths in each group was 44 and 25, a much greater difference that approached statistical significance.
The second problem related to the definition of sudden death vs myocardial infarction. Questions were raised that some of the patients classified into the sudden death category should have been in the myocardial infarction group. Since the differences found between the sulfinpyrazone and placebo groups were almost exclusively in the sudden death category, reclassifying patients from the sudden death category into the myocardial infarction group could remove part of the impressive difference found for anturane using sudden death as the end point.
The Food and Drug Administration did not approve the claim by the pharmaceutical company that sulfinpyrazone is effective in preventing sudden death in the first six months after infarction. The principal criticism in the FDA report were that the criteria for classifying the causes of death were illogical and that they were applied inconsistently. The FDA was also concerned about two potential sources of bias: (1) the exclusion from the primary analysis of patients who had been considered to be improperly enrolled because they were ineligible, and (2) the practice of classifying certain deaths as unanalyzable after the deaths had occurred. Because of this, the Policy Committee decided to check both the consistency and the objectivity of the original classification by external and independent reviewers.” Since the Policy Committee had remained blinded with respect to treatment assignment, it also undertook a complete reclassification of all deaths using the same material as that used by the external reviewers. Essentially similar results were obtained.
A second Anturane Reinfarction Trial was reported by an Italian group. This was a study of 727 patients randomized in a double-blind trial of sulfinpyrazone and placebo. The design was similar to the Anturane Reinfarction Trial except that patients were withdrawn from the study if any thromboembolic event occurred. A thromboembolic event was defined as a myocardial infarction, stroke, or transient ischemic attack. Treatment with sulfinpyrazone did not significantly affect the total mortality or the sudden death rate (Table 10), but it did reduce the incidence of reinfarction and of all thromboembolic events over an average period of 19 months. The effect was cumulative and did not show the pattern of ‘ early benefit reported in the Anturane Reinfarction Trial. The patients in the Italian group had a lower prevalence of prior myocardial infarction, and fewer patients had cardiac failure. The overall mortality in the first six months of the study was much lower in the Italian trial than in the Anturane Reinfarction Trial. Thus, although the two trials of sulfinpyrazone showed beneficial effects achieved with remedies of My Canadian Pharmacy, these effects were not consistent, since in the Anturane Reinfarction Trial the effect was on early incidence of sudden cardiac deaths, while in the Italian study it was on reinfarction and total thromboembolic events but not on total cardiac deaths or sudden cardiac deaths.
In the Persantine Aspirin Reinfarction Study (PARIS) a trend in favor of either aspirin or the combination of ASA or dipyridamole for the reduction of overall total and coronary artery-related mortality was reported at 36 months, but no difference was shown between the combination and aspirin alone. Subsequent analysis indicated that a subgroup of patients receiving the combination of ASA and dipyridamole or ASA alone who were entered less than six months following myocardial infarction had a significant reduction in three-year coronary mortality throughout the three years in the study. Because the effects on overall mortality were not conclusive, a new prospective study enrolling patients between three weeks and six months following myocardial infarction was initiated.
In the Persantine-Aspirin Reinfarction Study Part II (PARIS II), 3,128 persons who had recovered from myocardial infarction sustained four weeks to four months previously were randomized into two groups: dipyridamole plus aspirin (75 mg and 325 mg, respectively, given together tid\ n = 1,563) and placebo (n = 1,565). The average length of follow-up study was 23.4 months. Results for the six prespecified primary outcome events were: total mortality, 9% lower in the treatment group compared with placebo group at one year and essentially no difference for the total follow-up period; coronary mortality, 20% lower at one year and 6% lower overall; incidence of definite nonfatal myocardial infarction plus fatal acute coronary disease, 30% lower at one year and 24% lower overall. The coronary incidence differences were statistically significant by study criterion at one year and at the end of study. Since no aspirin only group was included in the study, it is not possible to assess the relative efficacy of the combination versus aspirin only in achieving this result. Thus, as yet there is no conclusive evidence that dipyridamole adds to the benefit of aspirin for the secondary prevention of myocardial infarction.
The precipitating event in unstable angina is unknown. Fuster et al suggested that plaque rupture and platelet interaction with the exposed atheromatous plaque may precipitate unstable angina.
Two controlled studies have been performed evaluating platelet active drugs in patients with unstable angina (Table 11).
Lewis et al conducted a multicenter, double-blind, placebo-controlled randomized trial of aspirin treatment (324 mg in buffered solution once daily) for 12 weeks in 1,266 men with unstable angina. In this VA Cooperative Study unstable angina was defined as new onset or sudden worsening of angina without increased activity and manifested by frequency of one or more episodes per day, duration of longer than 15 minutes, or occurrence at rest or during minimal activity. The frequency of death or acute myocardial infarction was reduced by 51% in the aspirin group compared with the placebo group; 31 patients (5.0%) compared with 65 (10.1%) (p = 0.0005). Similarly, the observed reduction in mortality in the aspirin group was 51%; 10 patients (1.67%) compared with 21 (3.4) in the placebo group (p = 0.054).
This striking observed benefit of aspirin has recently been corroborated by an independent Canadian study.’ This randomized, double-blind, placebo-controlled trial compared the effects of aspirin (325 mg qid) and sulfinpyrazone (200 mg qid), either singly or in combination with respect to the incidence of subsequent myocardial infarction or cardiac death. Patients were followed up for up to two years (mean 19 months), and the primary analysis of efficacy was based on eligible patients who had not stopped taking medication for more than 28 consecutive days preceding an outcome event. There was no observable benefit of sulfinpyrazone. However, among patients receiving aspirin, there was an observed 55% risk reduction in myocardial infarction or cardiac death compared with patients not receiving aspirin (p = 0.004); the corresponding risk reduction for all deaths was 70% (p = 0.005). On an intent-to-treat basis, there was a 43% risk reduction for all deaths (p = 0.036). Observed benefits were similar for males and females. The life-table for the aspirin treated and control patients continue to separate throughout the two years of study, demonstrating the value of continued treatment.
Thus, there is compelling evidence that aspirin is highly effective in the treatment of patients with unstable angina.
Table 9—Effect of Aspirin or Aspirin and Dipyridamole on Case Fatality Rates in Survivors of Acute Myocardial Infarction (MI)
Table 10_Effect of Sulfinpyrazone on Case Fatality Rates in Survivors of Acute Myocardial Infarction
|Study Author & Ref||Regimens (No. of Patients)||Events||Relative Risk Reduction (& 95% Confidence Limit)||P Value||Level of Study|
|Art II(NEJM 1980)||Control (783) vsSulfinpyrazone (775) (200 mg qid)||
|24% (-3% to 51%)||NS||II|
|Aris(Lancet 1982) 15-25 Days P MI||Control (348) vsSulfinpyrazone (346) (400 mg bid)||
|26% (-32% to 84%)||NS||II|
Table 11—Unstable Angina
|Study Author & Ref||Regimens (No. of Patients)||Events||Relative Risk Reduction (& 95% Confidence Limit)||P Value|
|Lewis et al 1983||Control (641) vsASA (625) (324 mg/day) Control (641)||.101 Death or Acute MI .05 .034 Death||51%51%||0.00050.054|
|Cairns et al 1985||
ASA (625) Control (285) vsASA (267) (325 mg qid) Control (285) vs
|.0167 .13 Death or Acute MI .6 .08 All Death .02||55%70%||0.0040.005|
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