The Platelet Inhibition and Patient Outcomes (PLATO) trial demonstrated that treatment with ticagrelor instead of clopidogrel in a broad population of patients with ACS substantially reduced the risk of death from vascular causes, myocardial infarction, or stroke, and reduced cardiovascular and total mortality at 12 months without increasing the risk of major bleeding.(1) Ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, provides faster, greater, and more consistent (interpatient) P2Y12 inhibition than clopidogrel.
In the recent issue of Circulation (2), the results of PLATO trial in relation to patients with renal disease were presented. 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.
Dose administration in the trial-
Ticagrelor - loading dose of 180 mg followed by 90 mg twice daily.
Clopidogrel- Patients randomized to clopidogrel who had not received clopidogrel for at least 5 days before randomization received a 300-mg loading dose of clopidogrel study drug followed by 75 mg daily. Others continued a maintenance dose of 75 mg daily as clopidogrel study drug.
All patients received acetylsalicylic acid unless intolerant.
Duration- Median duration of study treatment was 9.1 months.
Analyses of primary and secondary efficacy and safety events were performed in patient groups based on the cut point of CrCl of 60 mL/min, the cut point defining Chronic Kideny Disease (CKD) classes 3 and 4.
The numeric absolute (and relative) risk reductions of the primary composite end point and total mortality by ticagrelor versus clopidogrel were 4.7% (23%) and 4.0% (28%) in patients with CKD and 1% (10%) and 0.5% (11%) in patients with normal renal function.
The number needed to treat to prevent an additional event in patients with CKD was 21 (95% confidence interval [CI], 13 to 56) for the primary composite event and 25 (95% CI, 16 to 63) for total mortality.
In fact, ticagrelor reduced the primary composite end point and total mortality versus clopidogrel consistently, regardless of CrCl cutoff value for CKD, with progressively decreasing point estimates of the HR with decreasing cutoffs values of CrCl from 100 to 30 mL/min.
A smaller group, defined as those with CKD, was identified with the Modification of Diet in Renal Disease (MDRD) equation (n=2562). The numeric absolute (and relative) risk reduction of the primary composite end point by ticagrelor versus clopidogrel was 6.0% (29%) in patients with CKD and 1.1% (10%) in patients with normal renal function (P for interaction=0.03). For all-cause mortality, the corresponding numbers were 5.3% (36%) and 0.5% (9%) (P for interaction=0.02). After multivariable adjustment, the interaction term for the primary end point did not remain significant.
Major bleeding increased with decreasing calculated CrCl at entry similarly in the ticagrelor and clopidogrel groups. The incidence of major bleeding did not differ significantly between the ticagrelor and clopidogrel groups in patients with normal renal function or in patients with CKD. The incidence of PLATO-defined major and Thrombolysis in Myocardial Infarction (TIMI) major bleedings not related to CABG increased with lower levels of calculated CrCl at entry with numerically higher rates with ticagrelor versus clopidogrel in patients with CKD.
The incidence of fatal bleeding was numerically lower and the incidence of intracranial bleeding numerically higher in the ticagrelor group versus the clopidogrel group with no significant interactions with renal function. The adjusted HR for major bleeding in patients with CKD was 1.11 (95% CI, 0.91 to 1.37); in patients with normal renal function, the adjusted HR was 1.08 (95% CI, 0.95 to 1.22; P for interaction=0.78).
Dyspnea occurred significantly more often with ticagrelor compared with clopidogrel in patients with CKD (5% absolute increase) and in patients with normal renal function (6.2% absolute increase). The occurrence of ventricular pauses 3 seconds during the first week or 30 days later did not differ significantly between the randomized groups. There was a relative increase in serum creatinine from baseline to 12 months that was higher in patients with normal renal function than in those with CKD and significantly higher in the ticagrelor compared with the clopidogrel group, but there was no difference between the treatment groups at 1 month after the end of treatment . Dyspnea and ventricular pauses, potential adenosine-mediated side effects of ticagrelor, occurred with low frequency and did not increase with reduced renal function. Reduced mortality with ticagrelor occurred despite the fact that patients with CKD who initiated treatment later after randomization discontinued study treatment prematurely more often, leading to a shorter duration of therapy.
The authors have highlighted that the significant benefit of ticagrelor over clopidogrel in patients with CKD contrasts with lack of a benefit of clopidogrel versus placebo. In the Clopidogrel for Reduction of Events During Observation (CREDO) trial, clopidogrel versus placebo reduced the composite of death, myocardial infarction, and stroke in patients with normal renal function, but there was in fact a trend in the opposite direction with an absolute increased event rate in patients with mild or moderate renal dysfunction. In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, there was also a modest absolute and relative reduction in the primary ischemic end point with clopidogrel versus placebo among patients with renal dysfunction compared with those with normal renal function, although without any significant interaction.The authors have pointed out that the randomization was not stratified for renal function; therefore, some imbalance between the randomized groups may exist among patients with renal dysfunction.
The authors concluded that the present results provide clinical evidence that ticagrelor is a more effective antiplatelet agent than clopidogrel in patients with ACS, regardless of renal function, and that the benefits are larger at poor renal function and without any need for dose reduction to prevent major bleeding.
Ticagrelor provides an important opportunity to substantially improve outcome in patients with ACS and impaired renal function.
(1) http://www.nejm.org/doi/full/10.1056/NEJMoa0904327#ref11
(2) http://circ.ahajournals.org/cgi/content/full/122/11/1056#R1-933796
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