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Ticagrelor versus Clopidogrel in Acute Coronary Syndromes

To the Editor: In the Study of Platelet Inhibition and Patient Outcomes (PLATO), Wallentin et al. (Sept. 10 issue)1 found that in patients with acute coronary syndromes, the use of ticagrelor, as compared with clopidogrel, significantly reduced the rate of death, myocardial infarction, or stroke without increasing the rate of bleeding. Ticagrelor, a direct-acting oral antagonist of the adenosine diphosphate receptor, was associated with adverse events, including dyspnea, ventricular pauses, and increased levels of creatinine and uric acid. Although the mechanism of these effects is unknown, components of the molecular structure of ticagrelor are almost identical to those of adenosine, which can be degraded to uric acid, and it is conceivable that metabolites of ticagrelor activate adenosine receptors. It is well known that adenosine induces dyspnea by bronchoconstriction,2 depresses the atrioventricular node,3 and causes deterioration in renal function by arteriolar constriction.4 These adverse events were generally self-limiting, but discontinuation of the study drug because of adverse events occurred more frequently in the ticagrelor group than in the clopidogrel group. Since only 4.1 to 5.9% of the study patients had chronic renal disease, congestive heart failure, or obstructive pulmonary disease, the adverse effects of ticagrelor require further evaluation. Haruo Tomoda, M.D., Ph.D.
Tokyo Heart Institute Tokyo, Japan tokyoheart@abelia.ocn.ne.jp
1. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus 3. Lerman BB, Belardinelli L. Cardiac electrophysiology of aden-

osine: basic and clinical concepts. Circulation 1991;83:1499-509. 4. Gottlieb SS, Brater DC, Thomas I, et al. BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy. Circulation 2002; 105:1348-53.

To the Editor: As shown in the PLATO trial, the increased efficacy of ticagrelor while maintaining safety appears to offer significant advantages, including a mortality benefit, over currently available therapies for acute coronary syndromes.1 In the trial, patients who were not already receiving clopidogrel were given a 300-mg loading dose with an option of an additional 300-mg loading dose if they underwent percutaneous coronary intervention (PCI) beyond 24 hours after randomization. However, patients in the ticagrelor group apparently all received an additional bolus of that drug. It appears that fewer than 20% of patients may have received the additional loading dose of clopidogrel, and only 26% received a glycoprotein IIb/IIIa inhibitor. We are concerned that patients may have been inadequately treated with clopidogrel (either in dose or timing of administration) before PCI,2 and this discrepancy in loading between the two drugs, along with the pharmacothis weeks letters 2385 Ticagrelor versus Clopidogrel in Acute Coronary Syndromes 2388 Intestinal Transplantation 2389 The Prometheus Payment Model 2390 Long-Term Follow-up of Survival in Hodgkins Lymphoma

clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57. 2. Brown RA, Spina D, Page CP. Adenosine receptors and asthma. Br J Pharmacol 2008;153:Suppl 1:S446-S456.

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kinetics of clopidogrel metabolism, appear to favor ticagrelor.3 In addition, it is possible that since 46% of the patients were already receiving clopidogrel before randomization, the trial may have selected a subgroup of patients with clopidogrel resistance,4 thereby biasing the results in favor of ticagrelor. Robert S. Rosenstein, M.D. David Parra, Pharm.D.
Veterans Affairs Medical Center West Palm Beach West Palm Beach, FL robert.rosenstein@va.gov
1. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus

cardial Infarction (TIMI) criteria: 446 of 931 patients (47.9%) in the ticagrelor group and 476 of 968 patients (49.2%) in the clopidogrel group. Do the authors have an explanation for this unusual finding? Marco Cattaneo, M.D.
Universit degli Studi di Milano Milan, Italy marco.cattaneo@unimi.it Dr. Cattaneo reports receiving lecture fees from LillyDaiichi Sankyo, AstraZeneca, and the Medicines Company. No other potential conflict of interest relevant to this letter was reported.
1. Cattaneo M. New P2Y12 inhibitors. Circulation (in press). 2. Pickard AS, Becker RC, Schumock GT, Frye CB. Clopidogrel-

clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15. 2. James S, Akerblom A, Cannon C, et al. Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J 2009;157: 599-605. 3. Bates ER, Lau WC, Bleske BE. Loading, pretreatment, and interindividual variability issues with clopidogrel dosing. Circulation 2005;111:2557-9. 4. Kuliczkowski W, Witkowski A, Polonski L, et al. Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J 2009;30:426-35.

associated bleeding and related complications in patients undergoing coronary artery bypass grafting. Pharmacotherapy 2008; 28:376-92. 3. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15.

To the Editor: In the PLATO trial, the direct P2Y12 inhibitor ticagrelor, as compared with clopidogrel, decreased the incidence of death, myocardial infarction, or stroke and increased the incidence of major bleeding not related to coronary-artery bypass grafting (CABG) in patients with acute coronary syndromes. These results are compatible with the demonstration that adequate inhibition of P2Y12-dependent platelet function is observed in the vast majority of ticagrelor-treated patients, as compared with only 60 to 70% of clopidogrel-treated patients.1 Consistent with its faster offset of action, ticagrelor was as safe as clopidogrel for patients undergoing CABG surgery: similar rates of CABGrelated bleeding were observed, even though ticagrelor had been withheld for only 24 to 72 hours before surgery, as compared with clopidogrel, which had been withheld for 5 days. The surprising finding of the PLATO trial was the very high incidence of CABG-related major bleeding in the two study groups, as compared with that reported in other studies involving patients receiving P2Y12 inhibitors,2,3 according to Thrombolysis in Myo2386

To the Editor: Three randomized studies the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,1 the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with PrasugrelThrombolysis in Myocardial Infarction (TRITONTIMI) 38,2 and now the PLATO trial have shown the benefit of dual antiplatelet therapy in patients with acute coronary syndromes. In general, as the antiplatelet effect of a drug increases, so does the risk of bleeding.1,2 In the PLATO trial, ticagrelor appeared to offer a mortality benefit over clopidogrel without any attendant increase in bleeding. The incidence of bleeding and transfusion in patients receiving clopidogrel in the PLATO trial was more than double the rates in previous trials, regardless of the criteria that were used, a finding that is not readily explained (Table 1). More patients in the TRITONTIMI 38 trial underwent PCI and received GPIIb/IIIa inhibitors than in the PLATO trial, yet the rate of blood transfusion in the clopidogrel group in the PLATO trial was 8.9%, as compared with only 3.0% in TRITONTIMI 38. One potential explanation is that some patients in the PLATO trial may have received more than one antithrombotic agent, which exposed them to a greater risk of bleeding, as shown in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) study.3 The increased rate of bleeding in the clopidogrel group in the PLATO trial, as compared with previous data, needs to be clarified.

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Table 1. Comparison of Three Randomized Trials of Platelet Adenosine Diphosphate Receptor Antagonists in Patients with Acute Coronary Syndromes.* Intervention or Event CURE (N = 12,562) Placebo Percutaneous coronary intervention Use of glycoprotein IIb/IIIa inhibitor Use of heparin Unfractionated Low-molecular-weight Use of anticoagulant agent Death from cardiovascular cause Bleeding Major, according to study criteria Major or minor, according to TIMI criteria Requiring packed red-cell transfusion 2.7 1.2 2.8 3.7 1.1 4 2.5 5.0 4 1.7 3.8 3 11.6 7.9 8.9 11.2 7.7 8.9 73.1 73.1 NA 5.5 72.3 72.3 NA 5.1 66 9 100 2.1 65 8 99 2.4 56.8 51.6 113.1 4.0 56.3 50.7 111.6 5.9 10.7 7.2 Clopidogrel 9.6 5.9 TRITONTIMI 38 (N = 13,608) Prasugrel 99 54 Clopidogrel 99 55 percent 64.1 26.4 64.6 26.8 PLATO (N = 18,624) Ticagrelor Clopidogrel

* CURE denotes Clopidogrel in Unstable Angina to Prevent Recurrent Events, NA not available, PLATO Study of Platelet Inhibition and Patient Outcomes, and TRITONTIMI 38 Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with PrasugrelThrombolysis in Myocardial Infarction 38. In the CURE trial, the results are for a combination of unfractionated heparin and low-molecular-weight heparin.

Siddharth A. Wartak, M.D. Amir Lotfi, M.D. Michael Rothberg, M.D., M.P.H.
Baystate Medical Center Springfield, MA drwartak@gmail.com
1. The Clopidogrel in Unstable Angina to Prevent Recurrent

Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without STsegment elevation. N Engl J Med 2001;345:494-502. [Errata, N Engl J Med 2001;345:1506, 1716.] 2. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15. 3. Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004;292:45-54.

The authors reply: In the PLATO trial, ticagrelor therapy was associated with dyspnea that was unrelated to changes in cardiovascular or pulmonary function. More ventricular pauses were also noted during monitoring in the acute phase, without any associated clinical consequences. Slight transient elevations in levels of creatinine and uric acid were detected without clinical consequence; treatment benefits were greater in patients with

reduced renal function than in those with normal renal function. As indicated by Tomoda, the most likely mechanism for these side effects was a temporary increase in stimulation of adenosine receptors, probably caused by the hampering of reabsorption of endogenous adenosine in red cells.1 With respect to the comments of Rosenstein and Parra regarding the dose of clopidogrel: the protocol for our trial allowed for the use of higher doses of clopidogrel than those approved at the start of the trial. Thus, all patients in the clopidogrel group had the option of receiving an additional 300 mg of clopidogrel for PCI procedures at any time. Furthermore, 46% of the patients were pretreated with clopidogrel between the index event and randomization.2 This gave the clopidogrel group an additional advantage, considering the slower onset of the effect of clopidogrel, as compared with ticagrelor. Finally, a recently presented subgroup analysis of patients who were intended to undergo an invasive procedure indicated that the treatment effect was consistent regardless of additional clopidogrel loading. With respect to the comments of Cattaneo and Wartak et al.: in our study, all CABG-related events were independently adjudicated with the use of

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the same criteria for major bleeding as for non Lars Wallentin, M.D., Ph.D. CABG-related events (i.e., a drop in hemoglobin Uppsala Clinical Research Center of 30 g per liter or the need for transfusion of Uppsala, Sweden lars.wallentin@ucr.uu.se 3 units of blood). This explains the higher rate of CABG-related bleeding than in other trials. Hkan Emanuelsson, M.D., Ph.D. AstraZeneca Research and Development The patients in our study had all types of acute Mlndal, Sweden coronary syndromes, as compared with those in Robert A. Harrington, M.D. TRITONTIMI 38,3 which recruited patients mainDuke Clinical Research Institute ly from the catheterization laboratory, and in the Durham, NC CURE trial,4 which enrolled only patients with 1. Bjrkman J-A, Kirk I, van Giezen JJ. AZD6140 inhibits adenacute coronary syndromes without ST-segment el- osine uptake into erythrocytes and enhances coronary blood evation before the era of intense antithrombotic flow after local ischemia or intracoronary adenosine infusion. Circulation 2007;116:Suppl II:II-28. abstract. and invasive treatment. 2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus The most valid evaluation of a new treatment clopidogrel in patients with acute coronary syndromes. N Engl J is the within-trial relative difference with a stan- Med 2009;361:1045-57. dard therapy (e.g., clopidogrel) on top of optimal 3. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J background treatment. By that standard, the Med 2007;357:2001-15. PLATO trial showed that ticagrelor was associ- 4. The Clopidogrel in Unstable Angina to Prevent Recurrent ated with reductions in myocardial infarction and Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without STstent thrombosis and improvement in survival, segment elevation. N Engl J Med 2001;345:494-502. [Errata, N Engl as compared with clopidogrel therapy, without an J Med 2001;345:1506, 1716.] overall change in major bleeding.

Intestinal Transplantation
To the Editor: In the review article on intestinal transplantation by Fishbein (Sept. 3 issue),1 more information would allow a better comparison between home parenteral nutrition therapy and intestinal transplantation. In case series of unselected patients receiving home parenteral nutrition, survival was decreased by the inclusion of patients with contraindications for intestinal transplantation.2 Approximately 50% of deaths among patients receiving home parenteral nutrition are related to causes other than home parenteral nutrition or the underlying disease, whereas almost all deaths after intestinal transplantation are related to the transplant.3 The Intestinal Transplant Registry indicates that about 25% of recipients of intestinal transplants who are alive have partial graft failure or need graft removal. Specific tools are required to compare the quality of life of patients receiving home parenteral nutrition with that of patients after intestinal transplantation.4 In a prospective survey on the appropriateness of the indications for intestinal transplantation,3 liver failure related to home parenteral nutrition and major complications related to central venous catheters were the only factors associated with a significantly increased risk of death among patients receiving home parenteral nutrition. Thus, the factors reported in Table 1 of the article are criteria for patient referral to expert centers for intestinal failure, but not for direct referral for intestinal transplantation.5 Loris Pironi, M.D.
University of Bologna Bologna,Italy loris.pironi@unibo.it

Michael Staun, M.D., Ph.D.

Rigshospitalet Copenhagen, Denmark

Andr Van Gossum, M.D.

Free University of Brussels Brussels, Belgium
1. Fishbein TM. Intestinal transplantation. N Engl J Med 2009;

361:998-1008. 2. Pironi L, Hbuterne X, Van Gossum A, et al. Candidates for intestinal transplantation: a multicenter survey in Europe. Am J Gastroenterol 2006;101:1633-43. 3. Pironi L, Forbes A, Joly F, et al. Survival of patients identified as candidates for intestinal transplantation: a 3-year prospective follow-up. Gastroenterology 2008;135:61-71. 4. Jeejeebhoy KN. Treatment of intestinal failure: transplanta-

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