Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Reviparin reduced a composite endpoint of death, reinfarction, stroke, and ischemia at 7 and 30 days after acute MI

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ACP J Club. 2005 Jul-Aug;143:4. doi:10.7326/ACPJC-2005-143-1-004

Related Content in this Issue
• Companion Abstract and Commentary: A glucose-insulin-potassium infusion did not reduce mortality, cardiac arrest, or cardiogenic shock after acute MI


Clinical Impact Ratings

Hospitalists: 6 stars

Cardiology: 5 stars

Critical Care: 6 stars


Source Citation

Yusuf S, Mehta SR, Xie C, et al. Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation. JAMA. 2005;293:427-36. [PubMed ID: 15671427]


Abstract

Question

In patients with acute myocardial infarction (MI), does the low-molecular-weight heparin (LMWH), reviparin reduce death, reinfarction, stroke, and recurrent ischemia better than placebo?

Methods

Design: Randomized placebo-controlled trial with a partial 2×2 factorial design (Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation [CREATE]).

Allocation: {Concealed}†.*

Blinding: Blinded (clinicians, patients, {data collectors, and outcome assessors}†).*

Follow-up period: 30 days.

Setting: 274 centers in China and 67 centers in India.

Patients: 15 570 patients (mean age 59 y, 77% men) presenting with suspected acute MI and ST-segment elevation or new left bundle-branch block within 12 hours of symptom onset. Exclusion criteria included high risk for bleeding, recent major surgery or trauma, systolic blood pressure ≥ 180 mm Hg, severe anemia, hemorrhagic stroke within the past 12 months, oral anticoagulant therapy, heparin-induced thrombocytopenia, and pregnancy.

Intervention: Patients were stratified by center and allocated to reviparin, 3436 IU Ph Eur antiXa units (5153 IU in patients who weighed 50 to 75 kg and 6871 IU for > 75 kg) subcutaneously every 12 hours for 7 days (n = 7780), or placebo (n = 7790). Study drugs were started before or within 15 minutes of initiation of thrombolytic therapy.

Outcomes: A composite endpoint of 7-day death, reinfarction, and stroke; and the composite endpoint plus ischemia with electrocardiogram changes. Secondary outcomes were individual components of the composite endpoint, any ischemia within 7 days, and outcomes at 30 days.

Patient follow-up: 99.96% (intention-to-treat analysis).

Main results

The 2 composite endpoints occurred in fewer patients who received reviparin than in those who received placebo (Table). A reduction in the individual components of death and reinfarction also occurred with reviparin (Table). Groups did not differ for stroke (0.8% vs 0.6%, P = 0.26). Results were similar at 30 days (Table). Reviparin was associated with an early increase in life-threatening or major bleeding (Table).

Conclusion

In patients with acute myocardial infarction, reviparin reduced a composite endpoint of death, reinfarction, stroke, and ischemia and mortality alone at 7 and 30 days, but increased the risk for major bleeding.

*See Glossary.

†Information provided by author.

Source of funding: No external funding.

For correspondence: Dr. S. Yusuf, Hamilton General Hospital and McMaster University, Hamilton, Ontario, Canada. E-mail yusuf@mcmaster.ca.


Table. Reviparin vs placebo for acute myocardial infarction‡

Outcomes Follow-up Reviparin Placebo RRR (95% CI) NNT (CI)
Composite endpoint 7 d 9.6% 11% 13% (4.1 to 20) 73 (43 to 231)
30 d 12% 14% 13% (5.2 to 20) 59 (37 to 149)
Composite endpoint + ischemia 7 d 11% 13% 12% (4.0 to 19) 67 (40 to 207)
30 d 14% 16% 12% (4.5 to 18) 56 (35 to 147)
Death 7 d 8.0% 8.9% 11% (0.8 to 19) 107 (56 to 1548)
30 d 9.8% 11% 13% (4.2 to 20) 71 (43 to 224)
Reinfarction 7 d 1.6% 2.1% 24% (4.2 to 40) 201 (109 to 1283)
30 d 2.0% 2.6% 23% (4.6 to 37) 174 (96 to 926)
RRI (CI) NNH (CI)
Life-threatening or major bleeding 7 d 0.9% 0.4% 154% (65 to 291) 181 (123 to 323)

‡Abbreviations defined in Glossary; RRR, RRI, NNT, NNH, and CI calculated from data in article.


Commentary

In the first GUSTO trial, no benefit was seen from intravenous (IV) heparin compared with subcutaneous unfractionated heparin in patients receiving streptokinase for ST-elevation MI (1). Other, much smaller studies have suggested benefit from IV unfractionated heparin with more fibrin-specific agents, such as acylated plasminogen-streptokinase activator complex and tissue plasminogen activator, with regard to such surrogate endpoints as patency. Until now, no megatrial appropriately powered to detect a difference in mortality has compared an LMWH (or unfractionated heparin) with placebo when administered with a fibrinolytic agent. The CREATE trial is the first to show that the LMWH reviparin is superior to placebo in terms of clinical endpoints when administered with any of several fibrinolytic agents.

The pharmacokinetic properties of several of the LMWHs differ substantially from one another. Therefore, it is unclear if the demonstrated benefits of reviparin would be seen with other LMWHs. Reviparin is not available in the United States. Physicians practicing where it is available ought to administer reviparin over placebo. Whether reviparin would outperform other LMWHs, or IV unfractionated heparin with fibrin-specific lytics, remains unknown.

The CREATE trial was a partial factorial design. The other intervention evaluated was GIK. A remarkable similarity exists between studies of GIK in patients with acute ST-elevation MI and those examining the effect of magnesium in acute MI. A meta-analysis of smaller trials of magnesium in acute MI suggested an impressive reduction in mortality (odds ratio 0.44, 95% CI 0.27 to 0.71) (2). However, the massive fourth International Study of Infarct Survival (ISIS-4) trial randomized 58 050 patients with acute MI to IV magnesium or no magnesium and did not show a reduction in 30-day mortality with magnesium therapy. In fact, there was a trend toward increased mortality with magnesium (P = 0.07) (3).

The GIK story is similar to that of magnesium. A previous meta-analysis of 16 trials with a total of nearly 5000 acute MI patients showed an 18% mortality reduction with GIK therapy (4). However, the CREATE-ECLA trial, which enrolled 20 201 patients, failed to show any benefit with GIK. In the case of magnesium and GIK, the public was lucky. Neither magnesium nor GIK has been shown to be harmful (except for phlebitis in 3.9% from IV potassium). (Patients with kidney disease in whom magnesium might be harmful were excluded from the magnesium trials; those with kidney disease and hyperkalemia in whom GIK might be harmful were excluded from GIK trials). However, an unknown but undoubtedly large number of other therapies are routinely administered to patients on the basis of underpowered randomized trials or even less reliable observational studies and anecdotal experience. Therefore, perhaps the most important lesson from CREATE-ECLA is that well-designed, appropriately powered trials are needed to confirm benefit and identify the true risks associated with therapies. When we consider the recent example of hormone replacement therapy (5), it is quite likely that some therapies currently administered to untold numbers of patients on a daily basis are not only not beneficial, but are less innocuous than magnesium and GIK.

Peter B. Berger, MD
Duke Clinical Research Institute
Durham, North Carolina, USA


References

1. Califf RM, White HD, Van de Werf F, et al. One-year results from the Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (GUSTO-I) trial. GUSTO-I Investigators. Circulation. 1996;94:1233-8. [PubMed ID: 8822974]

2. Teo KK, Yusuf S, Collins R, Held PH, Peto R. Effects of intravenous magnesium in suspected acute myocardial infarction: overview of randomised trials. BMJ. 1991;303:1499-503. [PubMed ID: 1838289]

3. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58, 050 patients with suspected acute myocardial infarction. Lancet. 1995;345:669-85. [PubMed ID: 7661937]

4. Yusuf S, Mehta SR, Diaz R, et al. Challenges in the conduct of large simple trials of important generic questions in resource-poor settings: the CREATE and ECLA trial program evaluating GIK (glucose, insulin and potassium) and low-molecular-weight heparin in acute myocardial infarction. Am Heart J. 2004;148:1068-78. [PubMed ID: 15632895]

5. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33. [PubMed ID: 12117397]