Original Article
Reactivation of Unstable Angina after the Discontinuation of Heparin
N Engl J Med 1992; 327:141-145July 16, 1992
- Abstract
- Abstract
Background.
Heparin is an effective, widely used treatment for unstable angina. Among patients enrolled in a double-blind, randomized, placebo-controlled trial comparing intravenous heparin, aspirin, both treatments, and neither during the acute phase of unstable angina, we encountered patients in whom unstable angina was reactivated after heparin was discontinued.
Methods.
The study population included 403 of the original 479 patients in the trial who had completed six days of blinded therapy without refractory angina or myocardial infarction. After the discontinuation of therapy, clinical events, including reactivation of unstable angina and myocardial infarction occurring within 96 hours after hospitalization, were closely monitored.
Results.
Early reactivation occurred in 14 of the 107 patients who received heparin alone, as compared with only 5 patients in each of the other three study groups (P<0.01). These reactivations required urgent intervention (thrombolysis, angioplasty, or coronary-bypass surgery) in 11 patients treated with heparin alone, but in only 2 patients in the other groups combined (P<0.01 ). Four of the six patients who had a myocardial infarction during a reactivation of their disease were in the heparin group. Reactivations in this group occurred in a cluster a mean (±SD) of 9.5±5 hours after the discontinuation of the study drug but were randomly distributed over the initial 96 hours in the other three groups.
Conclusions.
Although heparin is beneficial in treating unstable angina, the disease process may be reactivated within hours of the discontinuation of this drug. Concomitant therapy with aspirin may prevent this withdrawal phenomenon. (N Engl J Med 1992;327:141–5.)
Media in This Article
Figure 1
Cluster Analysis of the Time to the Occurrence of Reactivation Events after the Discontinuation of the Study Drugs.Figure 2
Kaplan–Meier Event-free Curves for Patients in the Four Study Groups.Article Activity
- Article
BOTH aspirin and heparin favorably influence the clinical course of patients with unstable angina. Aspirin protects against myocardial infarction and death during the acute,1 intermediate,2 and chronic3 phases of the disease. Heparin confers this benefit during the acute phase1 , 4 and also reduces the incidence of recurrent refractory angina.1 , 5 The optimal duration of heparin therapy in unstable angina is unknown. Despite the widespread use of heparin in various thromboembolic disorders,6 no serious reactions have been reported after its discontinuation, and treatment failures have been attributed to subtherapeutic doses,7 , 8 inadequate duration of therapy,9 , 10 or resistance to heparin.6 Rarely, thromboembolism is associated with a heparin-induced, antibody-mediated injury to platelets and vascular endothelium.11
This report describes the reactivation of unstable angina and the occurrence of myocardial infarction after the discontinuation of heparin in a large clinical trial comparing aspirin, heparin, the combination of the two, and the use of neither during the acute phase of unstable angina.1
Methods
The study population, design, and results of the clinical trial have been described elsewhere.1 In brief, 479 men and women with a mean (±SD) age of 58± 10 years were enrolled as soon as possible after admission to the hospital for unstable angina.1 The average interval between the most recent episode of chest pain and the time of randomization was 7.9±8 hours, and nearly all the patients were recruited within 24 hours. Electrocardiographic changes suggestive of myocardial ischemia were detected in 76 percent of the patients. Serial determinations of cardiac enzymes revealed non—Q-wave myocardial infarctions at the time of entry into the study in 4 percent.
The study was double-blind and randomized with a 2-by-2 factorial design. The four study groups received the following treatments: (1) oral aspirin at a daily dose of 325 mg given twice a day, plus placebo heparin (the aspirin-alone group); (2) intravenous heparin given in a bolus dose of 5000 units followed by a continuous infusion to maintain the activated partial-thromboplastin time at 1.5 to 2 times the base-line values, plus placebo aspirin (the heparin-alone group); (3) a combination of aspirin and heparin at the above dosages (the combination group); and (4) placebo aspirin plus placebo heparin (the placebo group). Porcine heparin was used.
Study Design
The study was designed to allow the optimal detection of a treatment effect. The possibility that a reactivation of disease might occur after treatment was stopped was not anticipated in the study design; however, the methods of data collection were adequate for the phenomenon to be accurately characterized, since all the patients were in the hospital and under close medical supervision. The study was limited to the acute phase of unstable angina, when reactivations of disease are most common. The study end points — death, nonfatal myocardial infarction, and recurrent angina refractory to medical treatment — were tabulated up to the time during the hospitalization when decisions were made about the patients' long-term care, usually after coronary angiography. End-point events occurred in 20 of the 121 patients randomly assigned to aspirin (16.5 percent), 11 of the 118 randomly assigned to heparin (9.3 percent), 14 of the 122 randomly assigned to both aspirin and heparin (11.5 percent), and 31 of the 118 randomly assigned to placebo (26.3 percent). These patients were excluded from the present analysis, leaving at risk 101, 107, 108, and 87 patients in the four study groups, respectively.
According to the study protocol, the study medication was discontinued when the patient returned from coronary angiography. The prescription of further treatment was left to the discretion of the attending cardiologist, on the basis of the patient's clinical status and the angiographic findings. The study drugs were stopped abruptly, without tapering, and the patients were followed in the hospital. Open-label aspirin was administered a few hours before the discontinuation of the study drugs in 11 patients in the aspirin-alone group, 12 in the heparin-alone group, 12 in the combination group, and 11 in the placebo group.
Coronary arteriography was performed a mean of 6±3 days after enrollment in the study, a period that corresponded to the usual waiting period in our institution at the time the trial was performed. Arteriography was done on an emergency basis, however, in patients refractory to medical treatment.
Definition of Events
All the patients were evaluated daily in the hospital by one of the investigators and the attending physician. Clinical events during and after the study were recorded. The events considered to be end points and those indicating a reactivation of disease were as follows: refractory angina, defined as recurrent chest pain with ST-T changes despite optimal antianginal treatment; new myocardial infarction; and death. Recurrent unstable angina after the discontinuation of the study drugs was considered to be severe when an urgent intervention was needed (thrombolysis, emergency coronary angioplasty, or bypass surgery). Myocardial infarction was diagnosed when at least two of the following three criteria were present: prolonged chest pain; elevation of creatine kinase activity to two or more times the upper limit of normal, with abnormally high values for creatine kinase MB; and new Q waves. Reactivation events were considered "early" if they occurred within 96 hours after the discontinuation of the study drugs, and "late" if they occurred after 96 hours but before three months had passed. Early events were the principal focus of the present study.
Statistical Analysis
Data were collected prospectively on a Dataflex program (version 2.2) and transferred to a BMDP file for statistical analysis. In the assessment of reactivation events, the 76 patients who had end-point events during the trial were excluded. The base-line characteristics of the patients at risk for a reactivation of disease in the four study groups were compared by the t-test and chi-square statistics. Kaplan–Meier survival curves were constructed to provide an integrated analysis of events during the trial and of those occurring early and late after the discontinuation of the study drugs; the curves were compared by the Mantel–Cox statistic. The time of discontinuation was adjusted to day 7 for each patient so that the sequences of the reactivation events would be comparable. Fisher's exact test was also used to compare event rates in the heparin-alone group with those in the other groups. Event rates in the four groups were also assessed by the method of Mehta and Patel.12 The timing of events relative to the discontinuation of the study drugs was compared by the Kruskal—Wallis statistic and by the k-means method of Engelman and Hartigan for cluster analysis.13 Risk factors for reactivation events were identified by multiple logistic regression. All the statistical analyses were two-tailed. P values less than 0.05 were considered to indicate significance.
Results
Characteristics of the Patients
The clinical characteristics of the patients at risk for reactivation of unstable angina in the four study groups are compared in Table 1Table 1
Characteristics of the 403 Patients.*. The only significant difference was that there was less frequent involvement of the left circumflex coronary artery in the combination-therapy group. Otherwise, the groups were comparable with regard to base-line clinical characteristics, angiographic findings, and clinical course in the hospital during the study period.Reactivation of Disease
Events indicative of a reactivation of disease (unstable angina or myocardial infarction) occurred in 29 of the 403 patients during the first 96 hours after the cessation of the study drugs, for an overall incidence of 7.2 percent. The initial event was recurrent unstable angina in 27 patients, 4 of whom had myocardial infarctions. The other two patients had myocardial infarctions as isolated events; one of them died of cardiogenic shock.
The distribution of the reactivation events among the four treatment groups is shown in Table 2Table 2
Reactivation Events According to Study Group.. There was an excess of events in the heparin-alone group (14 of 107 patients, or 13 percent) as compared with the other three groups, each of which had 5 patients with a reactivation (P = 0.07 for the comparison of all groups with each other; P<0.01 for the heparin-alone group vs. the other groups combined). The reactivations were more likely to be severe in the heparin-alone group: 11 patients in this group required urgent intervention, as compared with only 2 patients in the other three groups combined (P<0.01). Four of the six myocardial infarctions occurred in the heparin group.Reactivation occurred earlier in the heparin-alone group — a median of 9.5 hours after the discontinuation of the study drugs, as compared with a median of 28 hours in the other three groups (P<0.05). Among the six patients with a myocardial infarction, symptoms began after 5, 5, 9, and 17 hours in the four patients taking heparin alone, after 21 hours in the patient taking aspirin alone, and after 12 hours in the patient receiving placebo. Cluster analysis revealed a principal grouping of reactivation events 9.5±5 hours after the study drugs were stopped. This cluster included 12 of the 14 patients with a reactivation in the heparin-alone group (sensitivity, 86 percent). The remaining 2 patients taking heparin and the 15 patients who had reactivations in the other groups were equally distributed in secondary clusters with no consistent pattern (Fig. 1Figure 1
Cluster Analysis of the Time to the Occurrence of Reactivation Events after the Discontinuation of the Study Drugs.).Figure 2Figure 2
Kaplan–Meier Event-free Curves for Patients in the Four Study Groups. shows curves for the probability that a patient would not have a reactivation of disease (i.e., remain "event-free") for the four study groups over the course of the trial, the first 96 hours after the discontinuation of the study drug (indicated in the figure by a rectangle), and the subsequent follow-up through the end of the third month. During the study period, the event rate was lower with heparin alone (relative risk as compared with placebo, 0.29; 95 percent confidence interval, 0.14 to 0.61) and with combination therapy (relative risk, 0.36; 95 percent confidence interval, 0.18 to 0.73). The event rate was intermediate with aspirin (relative risk, 0.56; 95 percent confidence interval, 0.30 to 1.05). The event-free curve dropped sharply soon after the discontinuation of the study drugs in the heparin-alone group, but not in the other three groups. Subsequently, the rate of decrease was low and was similar in the four study groups. Statistical comparisons of the four curves overall showed a significant benefit with treatment as compared with placebo (for aspirin alone, P = 0.035; for heparin alone, P = 0.023; for aspirin plus heparin, P = 0.003; and for any treatment, P = 0.002), with aspirin as compared with no aspirin (P = 0.035), and with heparin as compared with no heparin (P = 0.021). Analysis of the curves from day 7 onward showed a worse prognosis with heparin than with aspirin alone (P = 0.01), combination therapy (P = 0.02), placebo (P = 0.12), or the three groups combined (P = 0.004). There were no other significant differences between groups.Risk Factors for Disease Reactivation
Concomitant drug therapy during the study, the total duration of the study, and the activated partial-thromboplastin time in the two days before the discontinuation of heparin were the same in patients whether or not they had a reactivation (Table 1). Beta-blocker therapy was interrupted in one patient before a reactivation, and calcium-antagonist therapy in another. Coronary angioplasty and coronary-bypass surgery were not performed in these patients within 96 hours after the discontinuation of the study drugs except to treat severe reactivation.
A logistic-regression analysis that included all clinical and angiographic variables shown in Table 1 identified therapy with heparin alone as the most powerful predictor of reactivation (P = 0.009). Other independent predictors were more severe coronary-artery stenosis (P = 0.04), longer cumulative duration of anginal pain during the study (P = 0.04), and younger age (P = 0.06).
Discussion
In this clinical trial of patients with acute unstable angina, the discontinuation of heparin therapy an average of six days after its initiation resulted in the reactivation of the disease process, manifested clinically as recurrent unstable angina, myocardial infarction, or both. This clinical reactivation was not observed when aspirin was administered concomitantly with heparin. By contrast, during the first six days of the trial (the treatment phase), heparin therapy provided significant clinical benefit as compared with placebo.1
Incidence of Reactivation
The possibility of disease reactivation after the withdrawal of heparin is not usually considered in clinical practice, despite the widespread use of heparin in the prophylaxis and management of thromboembolic disorders.6 Only sporadic cases of reactivation have been described.14 However, closer scrutiny of the results of many other studies suggests that it may have been present. For example, the lack of efficacy of heparin alone and the efficacy of the combination of aspirin and heparin in one study of unstable angina could be explained by this phenomenon.15
In the present study, reactivation of unstable angina after the discontinuation of heparin was observed in 13 percent of the patients — an incidence three times higher than that in any of the other three study groups. The clustering of events 9.5 hours after the cessation of heparin and the greater severity of the reactivation events in the patients treated with heparin alone support the observation that the higher incidence of reactivation after the discontinuation of heparin is not a chance observation. On the basis of the cluster analysis, the true frequency of reactivation was estimated to range from 5 to 10 percent. The scattering of events considered to represent reactivations in the other three groups was more consistent with a random distribution, suggesting that they actually represented the natural course of the disease.
The reactivation of unstable angina after the cessation of heparin supports our earlier observation that heparin reduces the risk of myocardial infarction and helps prevent recurrent ischemia in patients with unstable angina. The persistence of this benefit for as long as three months indicates that heparin not only postpones events but also corrects the pathophysiologic process that causes instability in most cases. In some patients, reactivation of disease soon after the discontinuation of heparin suggests that they may require more than a few days of treatment or some other protective measures. Aspirin appears useful in this regard: no events occurred in the 12 patients assigned to receive heparin alone who nevertheless received aspirin before heparin was discontinued, and there was no excess of reactivation events in the combination-therapy group.
Mechanism of Reactivation
The study design allowed reactivation events to be detected after the discontinuation of the study drug, but it did not yield insights into the mechanisms involved. Any conclusion related to these mechanisms is therefore speculative. Reactivation could simply represent the reemergence of an ongoing thrombotic process that was only partially suppressed by heparin's inhibitory effect on thrombin. In addition, any residual thrombus would provide a strong thrombogenic stimulus to thrombus growth.16 , 17 In support of this hypothesis, the patients with reactivations of disease in this study had more severe ischemia-related coronary-artery stenoses and more angina during the study. Experimental models show that thrombin is an important mediator of platelet aggregation in coronary arteries with stenosis and arteries in which the endothelium has been injured18 , 19; antithrombin agents such as heparin can prevent the platelet-mediated cyclic variations in coronary blood flow in these models.20 Serotonin, thromboxane A2 inhibitors,21 and aspirin also have protective effects against platelet deposition.22 Thus, a likely explanation for the reactivation process is that heparin exerted a true protective effect, interfering with the natural history of unstable angina.
Reactivation could also be caused by the recurrence of a preexisting local or systemic hypercoagulable state. The fact that the event rate was higher after heparin was stopped than in the placebo-treated patients during the study may support this mechanism. Antithrombin III is consumed during the administration of heparin, and the plasma levels have been reported to be low for two to three days after the discontinuation of heparin.23 Such low levels of antithrombin III are associated with biochemical evidence of hyperactivity of factor Xa and, in familial aggregates, with a high risk of venous and occasionally arterial thrombosis.24 , 25 These low levels could also possibly limit the protective effect of glycosaminoglycans on the surface of endothelial cells and platelets.26 Although antithrombin III is a slow inactivator of activated blood factors in the absence of heparin, it accounts for approximately 75 percent of the plasma antithrombin activity27 and may have a role in disease processes involving damaged endothelium and residual intravascular clotting. Blood levels of fibrinopeptide A increase with the discontinuation of heparin in patients with acute myocardial infarction, thus documenting the generation of thrombin and possibly indicating that control of the disease process is incomplete.28 In these circumstances, thrombin can be released from the heparin—antithrombin—thrombin complex or from fibrin16 and can reactivate a process that has been only partly suppressed.
Reactivation appears to result from an imbalance between ongoing prothrombotic forces and decreasing antithrombotic activity after the withdrawal of heparin. The protection afforded by aspirin in this situation suggests a major role for thrombin and platelets in the reactivation of disease, especially at sites of severe stenosis, where shear forces are high.17 It may also suggest that reactivation is related to some of the direct effects of heparin on platelets.6
The beneficial effect of aspirin in preventing reactivation is analogous to the benefit when it serves as adjunctive therapy to fibrinolysis in acute myocardial infarction; the combination of aspirin with streptokinase reduced mortality twice as much as thrombolytic therapy alone, presumably by preventing recurrent infarction.29
These observations suggest that the clinician should be aware of the potential for reactivation in many situations; for example, in the timing of heparin cessation before bypass surgery, its cessation after an allergic reaction, or its cessation in patients unable to take aspirin. They also raise questions about the mechanism of reactivation, the optimal duration of heparin treatment in unstable angina, and the potential of newer antithrombin drugs to promote more rapid and complete lysis of the offending clot.30
Source Information
From the Montreal Heart Institute, 5000 Belanger St., Montreal, QC HIT 1C8, Canada, where reprint requests should be addressed to Dr. Théroux.
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