Si tengo que elegir, ¿quién se beneficiaría más de los nuevos antiagregantes?

Days After Randomization TRITON-TIMI 38: Primary end point (CV death, non-fatal MI or non-fatal stroke) and safety all ACS 15 Clopidogrel Prasugrel 12.1 (781) CV Death, NF MI or NF Stroke 9.9 (643) 10 p<0.001 End Point (%) ↓ 138 events ↑ 35 events 5 p=0.03 Non-CABG TIMI Major Bleeding 2.4 (146) [Figure 1A page 2009 Wiviott SD et al. N Eng J Med 2007;357:2001-2015] Bleeding definition: Bleeding complications were defined as: (i) major bleeding, intracranial bleeding or clinically overt bleeding associated with a decrease in haemoglobin >50 g/L; (ii) minor bleeding, clinically visible with a decrease in haemoglobin ≤50 g/L according to the modified criteria of thrombolysis in myocardial infarction (TIMI). Reference: Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357(20):2001-2015. 1.8 (111) 30 60 90 120 180 270 360 450 Days After Randomization Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period Wiviott SD et al. N Eng J Med 2007;357:2001–2015 Pras 00043901

PLATO: Primary end point (CV death, MI or stroke) at 12 months 15 11.7 10 9.8 End Point (%) 5 [Source: Wallentin et al., New Eng J Med. 2009;361:1045-1057, figure 1] Reference: Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361(11):1045-57. Clopidogrel Ticagrelor CV Death, MI or Stroke p<0.001 2 4 6 8 10 12 Months Wallentin et al. New Eng J Med 2009;361:1045–1057 Pras 00043901

PLATO: Safety outcomes (bleeding) Patients (%) [Source: Wallentin et al., New Eng J Med. 2009;361:1045-1057, table 4] Bleeding definitions: PLATO defined major life-threatening bleeding as fatal bleeding, intracranial bleeding, intrapericardial bleeding with cardiac tamponade, hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery, a decline in the hemoglobin level of 5.0 g per deciliter or more, or the need for transfusion of at least 4 units of red cells. PLATO defined other major bleeding as bleeding that led to clinically significant disability (e.g., intraocular bleeding with permanent vision loss) or bleeding either associated with a drop in the hemoglobin level of at least 3.0 g per deciliter but less than 5.0 g per deciliter or requiring transfusion of 2 to 3 units of red cells. PLATO defined minor bleeding as any bleeding requiring medical intervention but not meeting the criteria for major bleeding. TIMI bleeding complications were defined as: (i) major bleeding, intracranial bleeding or clinically overt bleeding associated with a decrease in haemoglobin >50 g/L; (ii) minor bleeding, clinically visible with a decrease in haemoglobin ≤50 g/L according to the modified criteria of thrombolysis in myocardial infarction (TIMI). Reference: Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361(11):1045-57. All Major Bleeding PLATO Definition All Major Bleeding TIMI Criteria Non-CABG-related Major Bleeding PLATO Definition Non-CABG-related Major Bleeding TIMI Criteria Wallentin et al. New Eng J Med 2009;361:1045–1057 Pras 00043901

Survival Benefit in PLATO TRITON All death PLATO Hazard ratio (95 % - confidence limit) Cardiovascular death HR 0,78 (0,69-0,89) Mortality. This hardest to get, and the unquestionably most important outcome measure represents the largest difference between trials. There were 107 more lives saved with ticagrelor than after conventional clopiodgrel (399 vs. 506), representing a highly significant absolute mortality reduction (hazard ratio [HR]=0.78; confidence interval [CI]=0.69–0.89; p<0.001) (2). This mortality advantage make ticagrelor a top achiever among any antiplatelet agent in a setting of a large randomised trial against an active comparator. In contrast, prasugrel failed to show any mortality benefit over clopidogrel in the TRITON trial (1). While cardiovascular deaths slightly trended in favour of prasugrel (133 vs. 150), however, excess in bleeding fatalities (21 vs. 5), and four extra cancerrelated deaths after prasugrel dilute the benefit almost completely. Moreover, final FDA notes from the Prasugrel Action Package revealed more deaths after prasugrel (5 vs. 2) in patients lost in follow- up without primary endpoints (4). In short, while the entire prasugrel benefit in TRITON is exclusively attributed to the reduction of non fatal MIs, in PLATO, the mortality reduction (107 deaths) numerically exceeds the MI prevention benefit (89 events), making it a hitherto unmatchable achievement (5), and representing the major clinical outcome difference between the two trials. 0.5 1 1.5 Study drug better Clopidogrel better Wiviott SD et al., N Engl J Med 2007; Wallentin L et al., N Engl J Med 2009 5

Power to detect reduction in mortality Relative risk reduction 20%, α = 0.05 TRITON PLATO Mortality of control group 2.4 % 5.1 % Number of patients per study group 6,800 9,333 Power 35% 91% Wiviott SD et al., N Engl J Med 2007; Wallentin L et al., N Engl J Med 2009 6

TRITON vs PLATO: Major Efficacy End Points Prasugrel Ticagrelor Hazard Ratio Primary Endpoint CV Death Nonfatal MI Nonfatal stroke All Cause Death Myocardial infarction. At a first glance, the overall nonfatal MI reduction looks more impressive in TRITON than in PLATO. Indeed, the benefit of prasugrel in MI reduction in TRITON is 23.2%, when second MI prevention benefit of ticagrelor in PLATO was “only” 16%. However, there is an important difference between trials. The PLATO MI rates are realistic, match well with other similar studies like CURRENT (6) and ACUITY (7), in contrast to TRITON, where MI adjudication is a matter of considerable controversy due to massive inclusion of extra events (8, 9), half of which were enzymatic or “chemical” MIs rather than real clinical events not identified by investigators, but still adjudicated (3, 4). Therefore, MI prevention in PLATO and TRITON should be judged not only by the absolute difference between the treatment arms both favouring novel antiplatelet agents, but also acknowledging that MI adjudication in PLATO was handled utilising realistic, strict universal acute MI definition (10) rather than inflated assessment of MIs adding enzymatic leaks and almost every ischaemic episode to the totality of evidence. Indeed, following the recent worldwide trend towards lower MI rates (11), a reduction from 6.9% in the clopidogrel arm to 5.8% after ticagrelor – especially late in the trial – unquestionably represents a solid achievement over both clopidogrel and prasugrel. Stent Thrombosis 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 HR Prasugrel/Ticagrelor Better Clopidogrel Better Wiviott SD et al., N Engl J Med 2007; Wallentin L et al., N Engl J Med 2009 7 7 7

TRITON TIMI-38: Stent Thrombosis ARC Definite + Probable Any Stent at Index PCI n=12,844 Clopidogrel 2.4 (142) 2 End Point (%) 74 events 1.1 (68) 1 Prasugrel Of note, the rate of definite or probable stent thrombosis, as defined by the Academic Research Consortium, was significantly reduced in the prasugrel group as compared with the clopidogrel group, (1.1% vs. 2.4%; hazard ratio, 0.48; 95% CI, 0.36 to 0.64; P<0.001). This observation extended to patients receiving bare metal stents alone (hazard ratio, 0.52; 95% CI, 0.35 to 0.77; P<0.001) as well as those receiving at least one drug-eluting stent (hazard ratio, 0.43; 95% CI, 0.28 to 0.66; P<0.001). HR 0.48 P<0.0001 NNT=77 30 60 90 180 270 360 450 Days ARC = Academic Research Consortium; PCI = percutaneous coronary intervention Wiviott SD et al. N Engl J Med. 2007;357:2001-2015.

Benefit of prasugrel in STEMI 15 CV death / MI / stroke Clopidogrel 12.4% 9.5% 10.0% 10 Endpoint (%) 6.5% Prasugrel 5 TIMI major non-CABG bleeds Prasugrel 2.4% 2.1% Clopidogrel 30 60 90 180 270 360 450 Days Montalescot G et al., Lancet 2009

Benefit of prasugrel in diabetics 18 Clopidogrel 17.0% 16 CV death / MI / stroke 14 12.2% 12 HR 0.70 P < 0.001 10 Prasugrel Endpoint (%) 8 NNT = 21 6 TIMI major non-CABG bleeds 4 Clopidogrel 2.6% 2 2.5% Prasugrel 30 60 90 180 270 360 450 Days Wiviott SD et al. Circulation 2008; 118: 1626-1636 10

PLATO

Diabetes N=4662 Primary endpoint PLATO Diabetes CV death, MI or stroke (%) No diabetes Number at risk Diabetes Ticagrelor 6999 6507 6407 6252 5143 3955 3191 Clopidogrel 6952 6434 6318 6153 5044 3869 3097 No diabetes Ticagrelor 2326 2113 2045 1959 1593 1199 953 Clopidogrel 2336 2084 2041 1968 1604 1225 975 Days after randomization

TRITON-TIMI 38 PLATO prasugrel clopidogrel ticagrelor Todos (n=13.608) No diabetes (n=10.462) Diabetes (n=3.146) (n=18.624) (n=13.951) (n=4.662) HR=0,81 (0,73-0,90) HR=0,86 (0,76-0,98) HR=0,70 (0,58-0,85) HR=0,84 (0,77-0,92) HR=0,83 (0,74-0,93) HR=0,88 (0,76-1,03) prasugrel clopidogrel ticagrelor % eventos isquémicos (muerte CV, infarto, ictus) En el estudio PLATO, al igual que en el TRITON-TIMI 38, se confirma el mayor riesgo de eventos tanto isquémicos como hemorrágicos en la población diabética con SCA y, consecuentemente, una mayor mortalidad a pesar de una más que aceptable adherencia a las guías clínicas de ambos estudios. Con la utilización de prasugrel en los diabéticos del estudio TRITON-TIMI 38 se consiguió reducir la tasa de eventos (muerte cardiovascular, infarto o ictus) en un 4,8% (el 30% de reducción relativa), mientras que con el ticagrelor en los diabéticos del PLATO esta reducción fue del 2,1% (el23% en términos relativos) y no alcanzó significación estadística. Aunque, al igual que en el TRITON-TIMI 38, en el estudio PLATO no hubo una interacción significativa entre el beneficio en la reducción de eventos isquémicos y la presencia o no de diabetes, los pacientes con valores de HbA1c por encima de la media consiguieron una reducción en la tasa de eventos cardiovasculares con ticagrelor del 2,8% (el 20% en términos relativos) que fue estadísticamente significativa. Hay que tener en cuenta que se trata de dos estudios con metodologías diferentes en cuanto a la valoración de eventos (sobre todo infartos y hemorragias) y, por lo tanto, las comparaciones entre los resultados de ambos han de hacerse con mucha cautela. Aun así, es tentador pensar que las diferencias observadas, sobre todo en infartos, puedan deberse en parte a la mayor dosis de carga de clopidogrel utilizada en los pacientes asignados a clopidogrel en el PLATO o al pretratamiento con clopidogrel en la mitad de los pacientes asignados a ticagrelor en ese estudio. Fernandez-Ortiz A, Vivas D, García-Rubira JC. Rev Esp Cardiol Supl. 2010;10:42D-48D

Ticagrelor vs clopidogrel in ACS in relation to renal function 22,0% 17,3% HR 0,77 (0,65-0,90) Ccr <60mL/min (n=3.237) 8,9% 7,9% HR 0,90 (0,79-1,02) Circulation. 2010 Sep 14;122(11):1056-67. Epub 2010 Aug 30. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. James S, Budaj A, Aylward P, Buck KK, Cannon CP, Cornel JH, Harrington RA, Horrow J, Katus H, Keltai M, Lewis BS, Parikh K, Storey RF, Szummer K, Wojdyla D, Wallentin L. Uppsala Clinical Research Center, Uppsala University Hospital, Uppsala, Sweden. Stefan.james@ucr.uu.se Comment in: Circulation. 2010 Sep 14;122(11):1049-52. BACKGROUND: Reduced renal function is associated with a poorer prognosis and increased bleeding risk in patients with acute coronary syndromes and may therefore alter the risk-benefit ratio with antiplatelet therapies. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor compared with clopidogrel reduced the primary composite end point of cardiovascular death, myocardial infarction, and stroke at 12 months but with similar major bleeding rates. METHODS AND RESULTS: Central laboratory serum creatinine levels were available in 15 202 (81.9%) acute coronary syndrome patients at baseline, and creatinine clearance, estimated by the Cockcroft Gault equation, was calculated. In patients with chronic kidney disease (creatinine clearance <60 mL/min; n=3237), ticagrelor versus clopidogrel significantly reduced the primary end point to 17.3% from 22.0% (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.65 to 0.90) with an absolute risk reduction greater than that of patients with normal renal function (n=11 965): 7.9% versus 8.9% (HR, 0.90; 95% CI, 0.79 to 1.02). In patients with chronic kidney disease, ticagrelor reduced total mortality (10.0% versus 14.0%; HR, 0.72; 95% CI, 0.58 to 0.89). Major bleeding rates, fatal bleedings, and non-coronary bypass-related major bleedings were not significantly different between the 2 randomized groups (15.1% versus 14.3%; HR, 1.07; 95% CI, 0.88 to 1.30; 0.34% versus 0.77%; HR, 0.48; 95% CI, 0.15 to 1.54; and 8.5% versus 7.3%; HR, 1.28; 95% CI, 0.97 to 1.68). The interactions between creatinine clearance and randomized treatment on any of the outcome variables were nonsignificant. CONCLUSIONS: In acute coronary syndrome patients with chronic kidney disease, ticagrelor compared with clopidogrel significantly reduces ischemic end points and mortality without a significant increase in major bleeding but with numerically more non-procedure-related bleeding. CLINICAL TRIAL REGISTRATION: URL:http://www.clinicatrials.gov. Unique identifier: NCT00391872. Ccr ≥60mL/min (n=11.965) James S, et al. Circulation 2010;122(11):1056-67.

Nuevos antiagregantes ¿a quién?: preguntas ¿quién es el mejor candidato para prasugrel? ¿quién es el mejor candidato para ticagrelor? ¿quién es el mejor candidato para clopidogrel? ¿puedo cambiar el tratamiento? ¿cómo? ¿nuevos en la fase aguda mejor, luego clopi? Si solo puedo disponer de uno, ¿cuál? Pretreatment  Intuitive with oral drug having slow onset of action Lack of rigorous studies supporting pretreatment with clopidogrel. Even the CREDO study was really a trial of loading dose vs. no loading dose, not a trial comparing pretreatment with a loading dose vs. a loading dose at the time of PCI Times to PCI are now shrinking and the risk of an ischaemic complication before cath is extremely low. The practical difference between upstream and downstream Rx diminishes A relevant proportion of the NSTE-ACS population does not need pretreatment as they undergo CABG or are medically managed The rapid onset of action of the oral P2Y12 inhibitors associated with the short delays to catheterisation, suggest that a pretreatment strategy in intermediate risk patients scheduled for early angiography has no room as demonstrated in ACCOAST