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The Big Heart Disease Lie

Cardiovascular Disease Causes and Possible Treatments

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trast, in patients who were not given aspirin, treatment with heparin was associated with a statistically nonsignificant 28% reduction in mortality, similar to the effect seen in the meta-analysis of trials in the pre-aspirin and prethrombolytic era.

When streptokinase is used as the thrombolytic agent, the data from the GUSTO trial demonstrated that treatment with iv heparin conferred no mortality benefit over highdose subcutaneous heparin (146). Since iv heparin is not superior to subcutaneous heparin (from GUSTO), and subcutaneous heparin is not superior to placebo (from GISSI-2 and ISIS-3), there is indirect data that iv heparin offers no advantage in patients receiving thrombolysis with streptokinase for acute myocardial infarction.

In contrast, when alteplase is used as the thrombolytic agent, iv heparin is a standard part of adjunctive therapy (4). There are two indirect lines of evidence that support this practice. First, several small trials (136,141,144) have shown improved infarct-related artery patency (defined as TIMI flow grade 2 or 3) when iv heparin is added to thrombolysis with alteplase (Table 4). More importantly, these trials have also demonstrated a higher percentage of patients achieve TIMI flow grade 3 with the addition of iv heparin to thrombolysis with alteplase. These trials were themselves too small to show a significant difference in mortality or reinfarction. However, extrapolating from the GUSTO-I data showing that TIMI flow grade 3 at 90 min is associated with lower mortality and better left ventricular function at 30 d (5), one can argue that the addition of iv heparin to thrombolysis with alteplase may improve patient outcome. Second, if one analyzes the patients receiving alteplase in GISSI-2, ISIS-3, and GUSTO-I, the mortality rates are 9.8% for alteplase alone, 9.6% for alteplase plus subcutaneous heparin, and 6.3% for alteplase plus iv heparin. Such comparisons are hazardous for several reasons. The mortality rates in general were lower in GUSTO-I than in GISSI-2 or ISIS-3 for comparable groups. More importantly, in GISSI-2 and ISIS-3, the "standard" alteplase infusion was used (100 mg over 3 h), whereas in GUSTO-I, an "accelerated" alteplase infusion (147) was used (100 mg over 90 min). Nonetheless, the lowest mortality rate with alteplase was achieved by giving it with iv heparin, and thus, this has become the standard of care.

Trials with More Intensive Intravenous Heparin Regimens. In GUSTO-I, 50% of patients failed to achieve therapeutic anticoagulation. Therefore, a more intensive iv heparin regimen (increasing the upper limit of the target activated partial thromboplas-tin time [aPTT] to 90 s and increasing the initial infusion of heparin to 1300 U/h for patients weighing 80 kg or more) was initially used in TIMI-9A (148), GUSTO-IIa (149), and HIT-III (150). This resulted in 20% more heparin being administered in GUSTO-IIa than in GUSTO-I. All three trials were stopped prematurely because of an increased rate of ICH and other major bleeding events. Whereas the rate of ICH was 0.7% in GUSTO-I, it was 1.9% in the heparin arm of TIMI-9A and 1.5% in the heparin arm of GUSTO-IIa (for the subset of patients receiving thrombolytic therapy for acute myocardial infarction); there were no ICHs in the heparin arm of HIT-III, but there was a 3.4% rate in the hirudin arm, prompting the termination of that trial. The mean aPTT of patients with ICH was 100 s in TIMI-9A and 110 s in GUSTO-IIa as compared to a mean aPTT of 85 s (both trials) for patients without ICH. An analysis of the aPTTs from patients enrolled in the GUSTO-I trial revealed a lower mortality was associated with aPTT at 12 h between 50 and 70 s; aPTTs higher than this were associated with an increased rate of moderate to severe bleeding, ICH, and, interestingly, reinfarction (151).

In summary, in patients ineligible for thrombolytic therapy, heparin is of proven benefit in patients unable to take aspirin and is of no proven benefit in those taking aspirin. For patients receiving thrombolytic therapy with streptokinase, there is no data that heparin, either subcutaneous or iv, offers any benefit. For patients receiving alteplase, heparin continues to be used based on angiographic data showing higher infarct-related artery patency, but clinical trials demonstrating decreased mortality or reinfarction are lacking. By extension from its use with alteplase, heparin is also routinely used with the new third-generation fibrinolytics reteplase and TNK-tPA. If heparin is to be used, it should be adjusted to achieve an aPTT between 50 and 70 s.

Direct Thrombin Inhibitors

Hirudin

Pharmacology. Hirudin is a naturally occurring anticoagulant derived from the saliva of the medicinal leech (Hirudo medicinalis) that has subsequently been produced via recombinant DNA technology (152). It is a 65-amino-acid protein with a molecular weight of 7000 Da that contains two domains: the N-terminal domain binds to and inhibits the active catalytic site of thrombin (153) and the C-terminal tail binds to the sub-

Fig. 14. Interaction between thrombin and direct thrombin inhibitors. Hirudin (A) and bivalirudin (B) bind to both the catalytic and substrate recognition sites. Argatroban (C) binds only to the catalytic site. All of the direct thrombin inhibitors can inactivate clot-bound thrombin and none of them requires the presence of ATIII.

Fig. 14. Interaction between thrombin and direct thrombin inhibitors. Hirudin (A) and bivalirudin (B) bind to both the catalytic and substrate recognition sites. Argatroban (C) binds only to the catalytic site. All of the direct thrombin inhibitors can inactivate clot-bound thrombin and none of them requires the presence of ATIII.

Fig. 15. Comparison of the inhibitory effects of hirudin against fluid phase (open bars) and clot-bound (solid bars) thrombin activity. Thrombin or fibrin clots were incubated with citrated plasma in the presence or absence of hirudin. FPA levels were then measured by radioimmunoassay, and the percent inhibition of FPA generation was calculated for each inhibitor concentration. Reproduced with permission from ref. 17.

Fig. 15. Comparison of the inhibitory effects of hirudin against fluid phase (open bars) and clot-bound (solid bars) thrombin activity. Thrombin or fibrin clots were incubated with citrated plasma in the presence or absence of hirudin. FPA levels were then measured by radioimmunoassay, and the percent inhibition of FPA generation was calculated for each inhibitor concentration. Reproduced with permission from ref. 17.

strate recognition site of thrombin (154) (Fig. 14). The apolar binding site of thrombin may also be involved in the interaction (119). Unlike heparin, hirudin is a direct thrombin inhibitor and, therefore, does not require the presence of ATIII to neutralize thrombin. Hirudin is uniquely specific for thrombin (155), does not cross-react with the antibodies responsible for HIT, and is not inactivated by platelet factor 4 or heparinases. Hirudin is an extremely potent antithrombin and can inactivate both fluid-phase and clot-bound thrombin, although it is less effective against the latter, requiring approx 10-fold higher doses to achieve comparable degrees of thrombin inhibition (Fig. 15) (17,156).

Clinical Data. After demonstrating promising results in two pilot studies when given as adjunctive antithrombin therapy with alteplase (TIMI-5) (157) and streptokinase (TIMI-6) (158), hirudin was compared to heparin in three phase III trials (TIMI-9A [148], GUSTO-IIa [149], and HIT-III [150]). In both TIMI-9A and GUSTO-IIa, hirudin was given as a 0.6 mg/kg iv bolus followed by an infusion at 0.2 mg/kg/h, while in HITIII, a different recombinant hirudin was used and at a slightly lower dose (0.4 mg/kg iv bolus followed by an infusion at 0.15 mg/kg/h). As stated above, these trials were stopped prematurely because of an unexpectedly high rate of ICH. Combining the data from the three trials, treatment with hirudin was associated with a higher rate of ICH (1.6 vs 0.9%) and a higher rate of major bleeding (10.8 vs 7.7%). Based on these data, the TIMI, GUSTO, and HIT investigators altered their anticoagulation protocols with a reduction in the hirudin and heparin doses in TIMI-9B and GUSTO-IIb and a change from alteplase to streptokinase and a change from iv to subcutaneous hirudin and heparin in HIT-4.

In TIMI-9B (159), 3002 patients with acute myocardial infarction were treated with aspirin and either alteplase or streptokinase (at the discretion of the treating physician) and were randomized within 12 h of symptoms to receive anticoagulation for 96 h with either hirudin 0.1 mg/kg iv bolus, followed by an infusion at 0.1 mg/kg/h, or heparin 5000 U iv bolus, followed by an infusion at 1000 U/h. Both anticoagulants were adjusted to achieve an aPTT of 55-85 s. At 24 h, there was a slightly higher rate of death or nonfatal myocardial infarction with hirudin (2.8 vs 2.3%). At 30 d, treatment with hirudin was associated with a 21% higher incidence of death (6.1 vs 5.1%), a 19% reduction in the rate of myocardial infarction (3.6 vs 4.4%), and a 9% higher incidence of the combined end point of death, recurrent myocardial infarction, congestive heart failure, or shock (12.9 vs 11.9%). None of these differences achieved statistical significance. There was also no significant difference in the rates of ICH or other major bleeding events.

In GUSTO-IIb (160), 12,142 patients with acute coronary syndromes were randomized to receive anticoagulation for 72 h with either hirudin or heparin, each dosed according to the same protocol used in TIMI-9B. Of the 12,142 patients, 4131 presented with ST-segment elevation and 74% of those patients received thrombolytic therapy with either alteplase or streptokinase (again, at the discretion of the treating physician). At 24 h, treatment with hirudin (for both ST-elevation and non-ST-elevation patients) was associated with a statistically significant 39% reduction in the combined end point of death or myocardial infarction (from 2.1 to 1.3%). At 30 d, for the patients with ST-segment elevation, there was only a 6% reduction in mortality (from 6.2 to 5.9%), an 18% reduction in myocardial infarction (from 6.0 to 5.0%), and a 14% reduction in the primary combined end point of death or myocardial infarction (from 11.3 to 9.9%). None of these differences achieved statistical significance. For patients with ST-segment elevation, there was no significant difference in the rates of ICH or of severe or moderate bleeding (although for all patients, treatment with hirudin was associated with a 14% higher rate of major bleeding).

In HIT-4, 1208 patients with acute myocardial infarction were treated with streptok-inase and were randomized to hirudin 0.2 mg/kg iv bolus, followed by 0.5 mg/kg sub-cutaneously 2X daily for 5 to 7 d, or a bolus of placebo, followed by heparin 12,500 U subcutaneously 2X daily (161). Thirty-day mortality and reinfarction rates were similar with a 6.8% mortality and a 4.6% reinfarction rate in the hirudin group compared to a 6.4% mortality and a 5.1% reinfarction rate in the heparin group. Data from the angiographic substudy revealed a trend towards higher rates of TIMI flow grade 3 at 90 min with hirudin than with heparin (41 vs 34%, p = 0.16) and data from the electrocardiogram (ECG) substudy demonstrated a higher rate of complete ST-segment resolution by 90 min with hirudin than with heparin (28 vs 22%, p = 0.05).

Thus, despite promising angiographic data, three large randomized controlled trials have failed to show any statistically significant benefit of hirudin over heparin in terms of mortality or reinfarction (although in the largest trial, GUSTO-IIb, there was a trend showing an approx 18% reduction in reinfarction). There are several possible reasons for the lack of a significant demonstrable benefit with hirudin in these trials (162). First, the trials may have been underpowered, given the relatively low event rates. Calculations by the TIMI-9B investigators, however, showed that the likelihood that a 25% relative superiority of hirudin over heparin failed to be detected in TIMI-9B is less than 1 in 1000 and that the likelihood that even a 10% relative superiority failed to be detected is 1 in 20. Second, hirudin may have been dosed inadequately. However, in GUSTO-IIa, despite a higher dose of hirudin, which was associated with an unacceptably high rate of ICH, the rate of death or myocardial infarction was 11.7% in the hirudin group. Third, the duration of antithrombin therapy may have been inadequate. There is, however, no indication that treatment for 96 h (in TIMI-9B) was clearly superior to treatment for 72 h (in GUSTO-IIb). Fourth, the effects of direct thrombin inhibitors, such as hirudin, may not be durable. In GUSTO-IIb, all of hirudin's beneficial effect on reducing the rate of death or reinfarction was evident at 24 h; subsequent to this, the event-rate curves neither converged nor diverged (this pattern, however, was not seen in TIMI-9B, in which hirudin was associated with mixed results in terms of the rate of death or reinfarction at 24 h). This potential lack of a durable effect has also been noted in other trials using thrombin inhibitors (163-165) and stands in contradistinction to the beneficial effects seen with the GP IIb/IIIa inhibitors, which persist even out to 3 yr (166). The mechanistic implication of this observation is that thrombin inhibitors may not be able to "passivate" the arterial surface in order to prevent the generation of platelet thrombi after the treatment is discontinued. Fifth, like heparin, hirudin is not able to inhibit clot-bound thrombin. Sixth, although hirudin may be a more potent inhibitor of thrombin activity, it may be a less potent inhibitor of thrombin generation. Prothrombin fragment 1.2 (F1.2) levels are used as a marker of thrombin generation, and fibrinopeptide A (FPA) levels are used as a marker of thrombin activity. Data show that heparin causes a greater reduction in F1.2 levels than hirudin does, whereas hirudin causes a greater reduction in FPA levels than heparin does (167,168), implying that heparin may possess a greater ability to decrease thrombin generation (potentially through its enhancement of ATIII's inhibition of factor Xa) and hirudin may possess a greater ability to decrease thrombin activity.

Bivalirudin

Pharmacology. Bivalirudin (Angiomax, formerly Hirulog) is a 20-amino acid synthetic peptide with a molecular weight of 873 Da that contains the [d] Phe-Pro-Arg-Pro sequence of the amino terminus of hirudin connected by a polyglycyl link to a 12-amino acid sequence from the carboxy terminus of hirudin (117,169). The former sequence binds to and blocks the catalytic site, while the latter sequence binds to and blocks the substrate recognition site (Fig. 14). Bivalirudin has been shown to be equally active against both fluid-phase and clot-bound thrombin (17), and it is not inhibited by platelet factor 4.

Clinical Data. After promising data was seen in a pilot angiographic study (170), Theroux and colleagues at the Montreal Heart Institute randomized 68 patients presenting with acute myocardial infarction and treated with aspirin and streptokinase to iv heparin, low-dose bivalirudin (0.5 mg/kg/h for 12 h, followed by 0.1 mg/kg/h for 4-6 days), and high-dose bivalirudin (1.0 mg/kg/h for 12 h, followed by a placebo infusion)

(171). The primary end point of TIMI flow grade 3 at 90 min was achieved in 31% of patients who received heparin, 85% of patients who received low-dose bivalirudin, and 61% of patients who received high-dose bivalirudin (p = 0.008).

The Hirulog Early Reperfusion/Occlusion (HERO) trial randomized 412 patients presenting with acute myocardial infarction and treated with aspirin and streptokinase to iv heparin, low-dose bivalirudin (0.125 mg/kg IV bolus, followed by an infusion at 0.25 mg/kg/h for 12 h, followed by an infusion at 0.125 mg/kg/h for <60 h), and high-dose bivalirudin (0.25 mg/kg IV bolus, followed by an infusion at 0.5 mg/kg/h for 12 h, followed by an infusion at 0.25 mg/kg/h for <60 h) (172). Again, the primary end point was achievement of TIMI flow grade 3 at 90-120 min. There was a statistically significantly higher percentage of patients achieving TIMI flow grade 3 with high-dose bivalirudin (48%) and low-dose bivalirudin (46%) than with heparin (35%) (p = 0.03). Major bleeding was significantly less in the low-dose bivalirudin group (14%) than in the high-dose bivalirudin (19%) or heparin (28%) groups (p < 0.01).

Based on the results of HERO-1, the HERO-2 trial was conducted in which patients undergoing fibrinolysis with streptokinase were randomized to bivalirudin (the same high-dose regimen used in HERO-1) or iv unfractionated heparin (173). Thirty-day mortality rates were similar in the bivalirudin (10.8%) and heparin (10.9%) arms and higher than the rates seen in other contemporary lytic trials (approx 6%). However, similar to the results seen with the direct thrombin inhibitor hirudin, treatment with bivalirudin was associated with a 30% reduction in the rate of reinfarction (1.6 vs 2.3%, p = 0.001).

Argatroban

Pharmacology. Argatroban is an arginine derivative tripeptide synthetic compound with a molecular weight of 527 Da that is structurally similar to fibrinopeptide A (117,174-176). Argatroban contains a sequence corresponding to the cleavage sequence in fibrinogen and inhibits thrombin by acting as a competitive antagonist, binding to the apolar binding site, and blocking the catalytic site (Fig. 14). Like hirudin, argatroban does not require the presence of ATIII to neutralize thrombin, and it is not inhibited by platelet factor 4 or heparinases. Argatroban is equally effective against fluid phase and clot-bound thrombin (Fig. 16) (156). This is in contrast both to heparin, which is largely ineffective against clot-bound thrombin, and to hirudin, which demonstrates reduced activity against clot-bound thrombin (17,156,177). This may be related to argatroban's relatively small size (Table 5), which may allow it to better penetrate into the interstices of a fibrin clot and, thus, more effectively inhibit fibrin-bound thrombin.

Clinical Data. In the Myocardial Infarction with Novastan and TPA (MINT) trial, 120 patients with acute myocardial infarction presenting within 6 h of symptom onset received alteplase and aspirin and were randomized to receive IV heparin (70 U/kg IV bolus, followed by an infusion at 15 U/kg/h), low-dose argatroban (100 ig/kg IV bolus, followed by an infusion at 1.0 ig/kg/min), or high-dose argatroban (100 ig/kg IV bolus, followed by an infusion at 3.0 ^g/kg/min) (178). Treatment with argatroban was associated with a trend towards higher rates of TIMI flow grade 3 at 90 min (58.7% in the high-dose argatroban group and 56.8% in the low-dose argatroban group compared to 42.1% in the heparin group; p = 0.13 and 0.20, respectively). In patients who received treatment between 3 and 6 h after the onset of symptoms, the superiority of argatroban was even more striking with TIMI flow grade 3 achieved in 57.1% of the high-dose argatroban patients vs in 20.0% of the heparin patients (p = 0.03). There were trends towards

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