Unfractionated Heparin

Of the available anticoagulant regimens for ACS, UFH is the oldest, most widely available, and until recently was the standard by which new anticoagulant agents were judged (18). Heparin was first identified in 1916. In 1939, investigators found that its anticoagulant properties required the presence of a cofactor that was later named antithrombin III (ATIII) (19). Heparin binds to the lysine site of ATIII and produces a conformational change at the arginine reactive center, converting ATIII from a slow to a rapid inhibitor of thrombin (factor IIa) (Fig. 1). Heparin then dissociates from the complex to be re-utilized (18,19). Commercial preparations of UFH are heterogeneous with compounds ranging in molecular weight from 3000-30,000 Da. One-third of these molecules with the essential pentasaccharide sequence bind ATIII and are responsible for the majority of heparin's anticoagulant effect. The remaining two-thirds have little anticoagulant effect at therapeutic doses (19).

The heparin-antithrombin III complex inactivates factors IIa (thrombin), Xa, XIIa, XIa, and IXa. Thrombin is 10X more sensitive to the heparin-ATIII complex than is factor Xa (19). However, the inactivation of thrombin requires that both ATIII and long-chain heparin bind to thrombin. The inactivation of factor Xa can be accomplished with short or long chains of heparin. Heparin moieties less than 5400 Da are unable to bind thrombin and ATIII simultaneously, but can bind factor Xa if they contains the correct pentasaccharide. As such, UFH exerts the majority of its anticoagulant properties through thrombin inactivation. Unfortunately, the anticoagulant effect of heparin is modified by platelets, fibrin, vascular surfaces, and plasma proteins. Platelet-bound factor Xa is inaccessible to UFH. Thrombin, when bound to fibrin, is also protected from

Fig. 1. The interaction of UFH, LMWH, and direct thrombin inhibitors with thrombin and factor Xa to inhibit thrombus formation.

inactivation by the heparin-ATIII complex. Finally, heparin binds to, and is inactivated by, a number of plasma proteins, including vitronectin and other acute phase reactant proteins (19). Therefore, despite its compelling anticoagulant properties, its use in the platelet-rich arterial thrombus may be somewhat limited.

From 1962-1973, six randomized trials encompassing 3800 patients with ACS were conducted involving UFH, as well as warfarin and phenindione, either alone or in combination (19). Pooling of the data from these trials showed a 22% reduction in total mortality (p < 0.002). Another overview of 5700 patients treated with heparin alone demonstrated a 16% reduction in mortality as well (20).

The first randomized, placebo-controlled trial of UFH in 1981 by Telford and Wilson (21) showed a significant reduction (vs placebo) in the incidence of MI (15 vs 3%) after 7 d of intravenous heparin. Theroux et al. (22) performed a placebo-controlled randomized trial evaluating aspirin alone vs heparin alone vs a combination of the two in 479 patients with acute UA. The incidence of refractory angina decreased by 63% in the heparin group and 53% in the combination group, but there was no change in the group receiving aspirin alone. The incidence of MI was reduced in the group receiving aspirin (3%, p = 0.01), UFH (0.8%, p = 0.001), and combination therapy (1.6%, p = 0.003) vs placebo (12%). As compared with aspirin, UFH was associated with a relative risk of 0.47 for refractory angina (p = 0.006), 0.25 for MI (p = 0.52), and 0.52 for any event (p = 0.10). The combination of aspirin and UFH was only slightly superior to aspirin alone and was worse than UFH alone. Thus, there was a trend towards the superiority of

UFH over aspirin in the treatment of UA. However, as a result of the efficacy of both drugs in UA, the study was under-powered to show a benefit of combination therapy.

Theroux et al. then continued their study (23), altering the design to evaluate aspirin alone in comparison with UFH alone, deleting the placebo and combination therapy arms. During the study period, MI occurred in 0.8% of patients in the UFH group compared with 3.7% in the aspirin group (p = 0.035). An extended factorial analysis of the 479 patients in the first trial and 245 patients in the second trial was performed. Four of 362 patients receiving UFH therapy experienced a fatal or nonfatal MI compared with 23 of 362 patients who did not (odds ratio 0.16, p < 0.005). Eleven of 366 patients who received aspirin suffered an event, compared with 16 of 358 patients who did not receive aspirin (odds ratio 0.66, p = NS). Bleeding complications were seen in 4 aspirin-treated patients compared with 15 heparin-treated patients (p = 0.008). The degree of risk reduction with UFH in comparison with aspirin exceeded 75%.

In the interim, the RISC Group (12) had published data showing that aspirin (75 mg daily), and not UFH (delivered in intermittent boluses), decreased the risk for MI in patients with UA. The results of this study should be qualified by the fact that heparin was delivered by intermittent boluses and the average dose of heparin was only 15,000 U/d. There was no adjustment of the dose on the basis of activated partial thromboplastin time (aPTT), making it likely that many patients had subtherapeutic anticoagulation. Additionally, patients were randomized up to 72 h after the last episode of chest pain, with the average time to randomization being 33 h. This resulted in the selection of a less acute cohort with lower-risk unstable coronary syndromes.

In another study of patients with refractory UA (24), where heparin was administered by continuous infusion, Neri Serneri et al. found that there was a significant decrease in the number of anginal attacks (71-77%), silent ischemia (84-94%), and total duration of ischemia (81-86%) compared with baseline (p < 0.001). Neither aspirin alone nor alteplase significantly reduced these endpoints.

In a later study (25), Neri Serneri et al. randomized patients with UA to subcutaneous UFH, intravenous heparin, or aspirin. The study design called for all patients to receive aspirin for 3 d prior to taking the study drug. Patients begun on heparin were taken off aspirin on d 4. After 72 h of the study drug, aspirin alone was found to have no effect on the number of anginal attacks, total ischemic episodes, or the duration of ischemia. Heparin, however, significantly lowered all three end points, whether given subcuta-neously or intravenously. Analysis would suggest that those receiving heparin actually also benefited from the residual effects of 3 d of aspirin. Similarly, Theroux et al. (26) observed a rebound of clinical symptoms after heparin discontinuation. Of note, this study also showed a trend suggesting that continuation of heparin therapy (12,500 IU subcutaneously daily) for at least 4 wk may be useful in patients with UA. A similar trend was not observed in the aspirin group.

In the Antithrombotic Therapy in Acute Coronary Syndromes (ATACS) Trial (27), 214 nonprior aspirin users with UA were randomized to aspirin (162.5 mg daily) alone, or aspirin plus UFH (aPTT adjusted) for 5 d followed by 12 wk of coumadin. Of the 214 patients, 147 had UA, 46 had a non-Q wave myocardial infarction (NQWMI), and 16 had a Q wave myocardial infarction (QWMI). At 14 d, 27% of patients receiving aspirin alone reached a primary end point of recurrent angina, or MI, or death, compared with 10% in the combination therapy group (p = 0.004). In the subset of patients with UA, a primary end point was attained in 29% of the aspirin group compared with 21% of the heparin group. Major bleeding was observed in 2.9% of the combination group, but not in those taking aspirin alone. By the end of12 wk of therapy, 25% of those solely on aspirin experienced a primary end point compared with 13% assigned to the aspirin and heparin group (p = 0.06). Pooling data from the ATACS, RISC, and Theroux studies produced an estimated relative risk of 0.44 for infarction or death among patients treated with combination anticoagulant and antiplatelet therapy in comparison with aspirin alone (27).

Holdright et al. (28), using Holter electrocardiogram (ECG) detection of ischemia, published results discordant with those above in a single-blind study of 285 patients with UA randomized to aspirin (150 mg daily) or aspirin plus intravenous aPTT-adjusted UFH. ST-segment monitoring was performed for the first 48 h of therapy. No significant difference between the two groups was noted for episodes of ischemia, total duration of ischemia, nor for secondary end points of MI or death.

Finally, in a meta-analysis (15) of 6 trials involving 1353 patients with UA and NSTEMI, the incidence of MI or death during combination therapy with heparin and aspirin was shown to be 7.9% compared to 10.4% in those on aspirin alone at 2 wk. This represents a risk reduction of 0.67 (p = 0.057). Risk of recurrent ischemic pain was 17.3% compared with 22.6% (p = 0.08), respectively. Major bleeding occurred in 0.4% and 1.5% (p = NS), respectively. Heparin had no effect on the rate of revascularization.

Thus, although there are some data showing that heparin is superior to aspirin alone in the treatment of patients with UA, the superiority of aspirin plus heparin over aspirin alone is not as strongly supported. Additionally, it is also clear that aspirin, when used in conjunction with heparin, reduces the incidence of rebound ischemic episodes that appear to cluster around 9.5 h after termination of the heparin infusion (27). Because UA represents a heterogeneous collection of ischemic pathology with varying degrees of risk for infarction and death, the potential benefit of heparin across these different groups probably differs. However, even when most would advocate the use of heparin, there is considerable disagreement as to the optimal duration of therapy. Although UFH continues to be viewed as a clinically important anticoagulant, the nomograms its use is based on need to be adjusted for the clinical variables that affect aPPT, the syndrome being treated, and any medications, other than UFH, that might affect hemostasis. Thus a guidance is required in view of the fact that different situations require different approaches regarding the use of UFH. For example, the dosage of UFH for the treatment of venous thromboembolic disease does not appear to be appropriate for subjects with ACS. This becomes important when UFH is used together with thrombolytic agents, because of the increased risk of intracranial hemorrhage. In view of this, recent American College of Cardiology/American Heart Association (ACC/AHA) Guidelines recommend that patients with acute MI receive an initial bolus of heparin at 60 U/kg (maximum, 4000 U), followed by alteplase (12 U/kg/h). Where intravenous heparin is given for the treatment of NSTEMI and UA, an initial bolus of 60-70 U/kg (maximum, 5000 U) followed by a 12-15 U/kg/h infusion is suggested. The aim is to reach an aPTT of 50-70 s (29).

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