Correspondence

Heparin versus Hirudin for Acute Coronary Syndromes

N Engl J Med 1997; 336:730-731March 6, 1997

Article

To the Editor:

The report by the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators comparing recombinant hirudin and heparin for the treatment of acute coronary syndromes (Sept. 12 issue)1 is important and timely. Unfortunately, the study design was biased against the standard heparin treatment. The patients receiving hirudin were given loading and maintenance doses based on body weight, whereas all the patients receiving heparin were given a fixed dose, regardless of their size. Since the average weights of the patients in each group were the same, this difference in specified dosage by the protocol could have led to the undertreatment of the patients in the heparin group. For example, according to one weight-based nomogram for the use of standard heparin to treat venous thrombosis, a loading dose is 80 units per kilogram of body weight, with a maintenance dose of 18 units per kilogram per hour.2 For a person weighing 76 kg, this would mean a loading dose of 6080 units, as compared with the fixed dose of 5000 units used in the GUSTO IIb study. Similarly, the maintenance dose of heparin for the same person would be 1368 units per hour, as compared with the 1000 units per hour used in this study. Thus, heparin treatment at a fixed dose results in an 18 percent reduction in the amount of heparin used in the loading dose and a 27 percent reduction in the amount used for maintenance therapy.

Because the study demonstrated significant improvement with hirudin as compared with heparin only in preventing myocardial infarction, the difference might have been abolished if weight-appropriate heparin therapy had been administered. Interpreting the final data in this manner suggests that hirudin and heparin are equivalent anticoagulant agents in treating acute coronary syndromes.

Alvin H. Schmaier, M.D.
University of Michigan, Ann Arbor, MI 49109

2 References

1. 1

   The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996;335:775-782
   Full Text | Web of Science | Medline

2. 2

   Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas S. The weight-based heparin dosing nomogram compared with a “standard care“ nomogram: a randomized controlled trial. Ann Intern Med 1993;119:874-881
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We appreciate Dr. Schmaier's comments and generally advocate a weight-adjusted dosing regimen for heparin. However, the findings in GUSTO IIb cannot be attributed to the use of insufficient amounts of heparin. When we attempted to give heparin more aggressively in the GUSTO IIa trial1 — at a level increased by approximately 25 percent, as Schmaier suggests — we encountered an unacceptable rate of intracerebral hemorrhage. Furthermore, both heparin and hirudin were administered on a double-blind, double-dummy basis, with careful adjustment of the dose so that the activated partial-thromboplastin time fell to between 60 and 85 seconds.

Heparin produced a higher level of anticoagulation than hirudin, as we pointed out in our primary report, but significantly more adjustments were required and there was much greater variation among patients. As we have previously shown, the anticoagulant effect of heparin is affected not only by weight, but also by age, sex, and cigarette-smoking status.2 Furthermore, higher activated partial-thromboplastin times have been associated with worse clinical outcomes in acute coronary syndromes.2 Accordingly, in GUSTO IIb we tested the maximal doses of heparin that were safely tolerated at levels of anticoagulation intended to be fully equivalent to those produced by hirudin.

The overall 11 percent reduction in the risk of death and myocardial infarction (at 30 days) achieved with hirudin provides support for the therapeutic effect of an agent that acts directly against thrombin, as compared with the conventional anticoagulant agent, which acts indirectly (since it depends on antithrombin III as a cofactor) and is ineffective against clot-bound thrombin.3 In summary, all the currently available data on the use of heparin in acute coronary syndromes provide evidence that more aggressive dosing leads to lesser efficacy and a higher rate of serious hemorrhagic complications.

Eric J. Topol, M.D.
Cleveland Clinic Foundation, Cleveland, OH 44195

Robert M. Califf, M.D.
Duke University Medical Center, Durham, NC 27705

Frans Van de Werf, M.D.
Catholic University of Leuven, B-3000 Leuven, Belgium

for the GUSTO IIb Investigators

3 References

1. 1

   The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation 1994;90:1631-1637
   Web of Science | Medline

2. 2

   Granger CB, Hirsh J, Califf RM, et al. Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction: results from the GUSTO-I trial. Circulation 1996;93:870-878
   Web of Science | Medline

3. 3

   The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996;335:775-782
   Full Text | Web of Science | Medline