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(Circulation. 2005;112:e282-e283.)
© 2005 American Heart Association, Inc.

Correspondence

Letters Regarding Article by Patti et al, "Randomized Trial of High Loading Dose of Clopidogrel for Reduction of Periprocedural Myocardial Infarction in Patients Undergoing Coronary Intervention: Results From the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) Study"

Pierluigi Tricoci, MD; Robert A. Harrington, MD

Duke Clinical Research Institute, Durham, NC

Marco Valgimigli, MD

Thoraxcenter Erasmus Medical Center, Rotterdam, The Netherlands, University of Ferrara, Ferrara, Italy

To the Editor:

Patti et al recently investigated the effect of pretreating patients undergoing percutaneous coronary intervention (PCI) with 600 mg of clopidogrel versus the conventional 300-mg dose.¹ Their results showed that the 600-mg dose reduces the composite of death, myocardial infarction, or target vessel revascularization up to 30 days after the procedure. The authors concluded that the study "demonstrated that the higher loading dose was more effective than the conventional dose in preventing ischemic complication." These findings were immediately accepted with enthusiasm.² Although this investigation is an important step in understanding the optimal loading dose for clopidogrel, we are concerned about a methodological limitation in the study.

The trial randomized 329 patients scheduled for coronary angiography who actually received a loading dose of either 600 mg or 300 mg clopidogrel. The authors reported only a per-protocol analysis in patients who actually underwent PCI. No safety or efficacy data were reported based on the intention-to-treat principle, which would be the most relevant information, because in clinical practice when the decision is made to pretreat with clopidogrel, the coronary anatomy is frequently unknown. Therefore, the decision to undertake clopidogrel pretreatment would be better understood based on the efficacy/safety data in the overall population, including CABG and medically managed patients. Thus, it would be of utmost interest to know the adjusted odds ratio for the primary end point.

The trial presents other methodological issues as the sample size calculated on the expected rate of any periprocedural CK-MB elevation instead of the major adverse cardiovascular events, which is referred to as the primary end point throughout the article and the fact that the logistic regression model "assessing the risk of the primary end point according to potential confounding" announced in the Methods is not shown anywhere in the article. Finally, the results presented cannot be conclusive because the 95% CI of the unadjusted OR is wide and entails a marginal potential advantage of the 600-mg dose (OR 0.31, 95% CI 0.09 to 0.95)

If the evidence of the efficacy of clopidogrel pretreatment is weak overall, mainly based on a post-hoc analysis, then the evidence that 600 mg is the optimal dose is negligible. The results of the ARMYDA-2 trial support the need of a well-designed and properly powered trial to answer the question whether 600 mg of clopidogrel as the loading dose is indicated in clinical practice.

	References

Top References References  References

 

1. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention. Results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation. 2005; 111: 2099–2106.[Abstract/Free Full Text]
   
2. ARMYDA-2: 600-mg Clopidogrel Preferable Pre-PCI. Available at: http://www.theheart.org/viewArticle.do?primaryKey=398589&from=/searchLayout.do. Accessed October 10, 2005.
   

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Theresa M. Palabrica, MD; Paul B. Burton, MD, PhD

Millennium Pharmaceuticals, Inc, Cambridge, Mass

To the Editor:

The Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty (ARMYDA-2) study reported that pretreatment with a 600-mg loading dose of clopidogrel 4 to 8 hours before percutaneous coronary intervention (PCI) resulted in significant reductions in periprocedural myocardial infarction (MI).¹ In the accompanying editorial,² Williams stated that these data, together with a recent report from Kastrati et al,³ suggest that glycoprotein (GP) IIb-IIIa inhibitors are no longer essential in treating patients undergoing PCI.

Multiple clinical factors may have an impact on prognosis, including severity of ST depression, elevated troponin, anatomic lesion characteristics and location, and presence of comorbidities including diabetes, multivessel coronary artery disease, and renal insufficiency. Little information on higher-risk patients can be derived from ARMYDA-2, yet these patients represent a substantial percentage of those undergoing PCI. The 4- to-8-hour pretreatment period further minimizes the applicability of this regimen because some patients who would ideally undergo immediate intervention may be forced to delay treatment to ensure adequate clopidogrel activity. These considerations suggest that the results of ARMYDA-2 are applicable only to low-risk patients.

Because ARMYDA-2 was conducted in Italy, these results must also be interpreted with respect to current practices in the United States. Only 20% of patients in ARMYDA-2 received drug-eluting stents (DES), whereas most patients in the United States currently receive DES. Widespread adoption of the ARMYDA-2 regimen may negatively affect overall outcomes when considered in light of the expanding use of DES in revascularization of lesions of greater complexity in smaller-caliber vessels.

Large randomized studies of GP IIb-IIIa inhibitors consistently show substantial reductions in risk of death, MI, and target vessel revascularization across a broad range of patient populations. In a meta-analysis of randomized trials enrolling >32 000 patients, GP IIb-IIIa inhibitors were associated with both significant reduction in the risk of mortality at 48 to 96 hours and significant benefit at 48 to 96 hours, 30 days, and 6 months for the combined end point of death and MI and the composite end point of death, MI, or revascularization.⁴ Current guidelines recommend the use of GP IIb-IIIa inhibitors in most patients undergoing PCI.

Unless the benefits reported in ARMYDA-2 can be reproduced in a clinically representative population, GP IIb-IIIa inhibitors should remain integral to the preferred treatment regimen for the majority of patients undergoing PCI.

	References

Top References References  References

 

1. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention. Results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation. 2005; 111: 2099–2106.[Abstract/Free Full Text]
   
2. Williams DO. Clopidogrel pretreatment for percutaneous coronary intervention: double, double, dose in trouble? Circulation. 2005; 111: 2019–2021.[Free Full Text]
   
3. Kastrati A, von Beckerath N, Joost A, Pogatsa-Murray G, Gorchakova O, Schomig A. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation. 2004; 110: 1916–1919.[Abstract/Free Full Text]
   
4. Kong DF, Califf RM, Miller DP, Moliterno DJ, White HD, Harrington RA, Tcheng JE, Lincoff AM, Hasselblad V, Topol EJ. Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease. Circulation. 1998; 98: 2829–2835.[Abstract/Free Full Text]
   

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Response

Giuseppe Patti, MD; Leonardo Lassandro Pepe, MD; Germano Di Sciascio, MD

Department of Cardiovascular Sciences, Campus Bio-Medico University, Rome, Italy

Giuseppe Colonna, MD; Antonio Montinaro, MD

Interventional Cardiology Unit, Vito Fazzi Hospital, Lecce, Italy

Vincenzo Pasceri, MD, PhD

Interventional Cardiology Unit, San Filippo Neri Hospital, Rome, Italy

We agree with Dr Palabrica that the population of ARMYDA-2, ¹ similar to that of the first ARMYDA trial,² is at moderate risk (ie, STEMI were excluded). However, 25% of patients had acute coronary syndromes (ACS), 66% had lesions B2-C, and 30% were diabetic, suggesting variable degrees of clinical and/or angiographic complexity. We acknowledge the efficacy of GPIIb-IIIa inhibitors in patients undergoing PCI, but we made no statement suggesting that GPIIb-IIIa inhibitors are no longer essential in treating such patients. To the contrary, we explicitly state that the 600-mg loading dose may be indicated on top of the optimal pharmacological regimen available in specific practice settings, including GPIIb-IIIa, when needed. Of course, whether higher loading doses of clopidogrel may do away with the need for GPIIb-IIIa in ACS including STEMI, will need to be tested in head-to-head comparisons, and we are sure it will be done eventually.

Our response to Dr Tricoci is that ARMYDA-2 was designed to test the effectiveness of higher loading doses of clopidogrel in patients undergoing PCI. However, the safety of this regimen was also evaluated in randomized patients indicated for surgery or medical therapy after coronary angiography. In fact, although it would be impossible to assess the efficacy of a higher clopidogrel loading regimen in reducing procedural ischemic complications in patients not undergoing PCI, we reported no increased risk of perioperative bleeding in the 600-mg patients undergoing elective surgery and no adverse events in patients treated medically.

Logistic regression data and adjusted odds ratios for the primary end point are indeed reported in our article (see Figure 5). Finally, the limitations of the study, including the use of a surrogate end point to calculate sample size, are clearly discussed in the text.

Perhaps the motives for "the surprising enthusiasm" generated by ARMYDA-2 are that this is the first study to provide evidence that 600-mg clopidogrel loading dose pre-PCI (already known to provide faster and more pronounced antiaggregation) confers clinical benefits compared with the conventional 300-mg regimen; accordingly, it is no surprise that the new European Society of Cardiology guidelines have incorporated the indication for 600-mg clopidogrel loading before PCI, recommending the 300-mg regimen only when pretreatment can be performed >6 hours before the procedure.³

	References

Top References References  References

 

1. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention. Results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation. 2005; 111: 2099–2106.[Abstract/Free Full Text]
   
2. Pasceri V, Patti G, Nusca A, Pristipino C, Richichi G, Di Sciascio G. A randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention. Results from the ARMYDA study. Circulation. 2004; 110: 674–678.[Abstract/Free Full Text]
   
3. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Guidelines for Percutaneous Coronary Interventions. Eur Heart J. 2005; 26: 804–847.[Free Full Text]
   

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tricoci, P. Articles by Pasceri, V. Search for Related Content PubMed PubMed Citation Articles by Tricoci, P. Articles by Pasceri, V. Related Collections Secondary prevention Coagulation Other anticoagulants Platelet function inhibitors Catheter-based coronary interventions: stents Platelets Related Article