Platelet Inhibition And Patient Outcomes Research Articles

Challenging the FDA Black Box Warning for High Aspirin Dose With Ticagrelor in Patients With Diabetes

Ticagrelor, a novel reversible antiplatelet agent, has a Food and Drug Administration (FDA) black box warning to avoid maintenance doses of aspirin (ASA) >100 mg/daily. This restriction is based on the hypothesis that ASA doses >100 mg somehow decreased ticagrelor’s benefit in the Platelet Inhibition and Patient Outcomes (PLATO) U.S. cohort. However, these data are highly postrandomized, come from a very small subgroup in PLATO (57% of patients in the U.S. site), and make no biological sense. Moreover, the ticagrelor-ASA interaction was not significant by any multivariate Cox regression analyses. The Complete Response Review for ticagrelor indicates that for U.S. PLATO patients, an ASA dose >300 mg was not a significant interaction for vascular outcomes. In the ticagrelor-ASA >300 mg cohort, all-cause and vascular mortality were not significantly increased (hazard ratio [HR] 1.27 [95% CI 0.84–1.93], P = 0.262 and 1.39 [0.87–2.2], P = 0.170), respectively. Furthermore, for major adverse cardiovascular events (MACEs), 30-day all-cause mortality, and 30-day vascular mortality, the strongest interaction is the diabetes-ASA interaction. That is, patients who had diabetes had significantly fewer MACEs through study end (0.49 [0.34–0.63], P < 0.0001), significantly less 30-day all-cause mortality (0.33 [0.20–0.56], P < 0.0001), and significantly less 30-day vascular mortality (0.35 [0.22–0.55], P < 0.0001), respectively, when given high-dose (300–325 mg) ASA, regardless of treatment (clopidogrel or ticagrelor) assignment. The black box warning for the use of maintenance ASA doses >100 mg with ticagrelor is inappropriate for patients with diabetes and not evidence based.

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

The Power of More Than One

There is widespread recognition of the increasing challenge of conducting adequately powered clinical trials in cardiovascular medicine.1 Given the broadening gap between guideline-based recommendations and the level of evidence supported by trials, this matter is a central priority. Two fundamental properties characterize the contemporary assessment of cardiovascular clinical trials. First, they are generally designed to evaluate the time to first event between the study arms. Second, different clinical events, presumed to be related to the targeted disease of interest, are commonly combined to form a composite end point.2 This approach increases the number of events observed during follow-up, usually but not always enhancing the statistical power and efficiency of clinical trials (ie, reducing the number of patients required). Article see p 673 Despite these established analytic techniques, several potential liabilities exist. The first event within a composite end point may not reflect the most clinically important or relevant one. Thus, incorporating subsequent events seems rational to provide a more comprehensive perspective of disease burden or therapeutic efficacy. This would also be timely, given that the recognition of recurrent events has emerged as a matter of increasing interest to patients, healthcare investigators, providers, and payers. The interpretation of composite end points can be perplexing, particularly when the directions of the individual components differ.3 In this issue of Circulation , Kohli et al4 address recurrent multiple events in the recent Platelet Inhibition and Patient Outcomes (PLATO) trial. The PLATO trial definitively demonstrated a treatment benefit of ticagrelor compared with clopidogrel in the …

Ticagrelor: A new antiplatelet drug for acute coronary syndromes

Coronary heart disease and acute coronary syndrome (ACS) are a significant cause of morbidity and mortality all over the world. Antiplatelet agents play an essential role in the treatment of acute coronary syndrome (ACS), usually with aspirin and a thienopyridine. Currently, clopidogrel, a second generation thienopyridine, is the main drug of choice, and the combination of aspirin and clopidogrel is administered orally for the treatment of ACS. Clopidogrel, the most commonly used thienopyridine, is limited by a high degree of interpatient variability and inconsistent inhibition of platelets. Ticagrelor, a new, oral, direct-acting P2Y12 receptor antagonist, produces a more profound and consistent antiplatelet effect than clopidogrel. The U.S. Food and Drug Administration approved Ticagrelor on July 20, 2011. Furthermore, ticagrelor has at least one active metabolite, which has pharmacokinetics that are very similar to the parent compound. Therefore, ticagrelor has a more rapid onset and more pronounced platelet inhibition than other antiplatelet agents. The safety and efficacy of ticagrelor compared with clopidogrel, in an ACS patient, has been recently evaluated by the PLATelet inhibition and patient Outcomes (PLATO) trial. Clinical studies of patients with both ST-elevation and non-ST-elevation ACS have shown that ticagrelor, when compared with clopidogrel, reduces the rates of vascular death and myocardial infarction. The clinical data currently available indicate that ticagrelor is a promising option for the treatment of patients with ACS and may be of particular use in those at high risk for ischemic events or in those unresponsive to clopidogrel.

Ticagrelor: The first approved reversible oral antiplatelet agent.

Platelet aggregation plays an important role in the pathophysiology of acute coronary syndrome (ACS). Aspirin is the most widely used antiplatelet agent and acts by inhibiting thromboxane A2-induced platelet activation. But it does not prevent platelets activation and aggregation by other signaling pathways like adenosine diphosphate (ADP) and Glycoprotein IIb/IIIa. Ticagrelor is the first oral reversible ADP (P2Y12) receptor antagonist. As compared to clopidogrel, ticagrelor has rapid onset as well as offset of action because of its reversible binding to P2Y12 receptor. It has potential to change the standard drug therapy of patient of ACS as shown in Platelet inhibition and patient outcomes (PLATO) trial, but long-term studies are required to further evaluate its efficacy and safety in these patients.

Reduction in First and Recurrent Cardiovascular Events With Ticagrelor Compared With Clopidogrel in the PLATO Study

We sought to evaluate the effect of potent platelet inhibition after acute coronary syndrome on total (ie, first and recurrent) occurrences of any of the primary outcome events (e.g., cardiovascular death, myocardial infarction, and stroke) as well as on other ischemic events, such as urgent revascularization, (severe) recurrent ischemia, transient ischemic attacks, and arterial thrombotic events. In the PLATelet inhibition and patient Outcomes (PLATO) study, 18 624 patients presenting with acute coronary syndromes randomly received ticagrelor (n=9333) or clopidogrel (n=9291). Cox proportional hazard models were used to calculate time to first event and hazard ratios. Total events were compared using a Poisson regression model, and time to second event or death was calculated with the Wei Lin Weissfeld method. Patients randomized to ticagrelor had 1057 total primary end point events versus 1225 for patients on clopidogrel (rate ratio, 0.86; 95% confidence interval, 0.79-0.93; P=0.003). The number of additional events was numerically lower for ticagrelor (189 versus 205; P=0.40), resulting in a hazard for time to second event/death of 0.80 (95% confidence interval, 0.70-0.90; P<0.001) and a number needed to treat of 54. For cardiovascular death/myocardial infarction/stroke/(severe) recurrent ischemia/transient ischemic attack/arterial thrombotic events, total events were fewer with ticagrelor (2030 versus 2290; rate ratio, 0.88; 95% confidence interval, 0.82-0.95; P<0.001), with fewer recurrent events with ticagrelor (740 versus 834; P=0.01) and a highly significant concurrent reduction in hazard for time to second event or death of 0.83 (95% confidence interval, 0.75-0.91; P<0.001). Recurrent PLATO major or Thrombolysis in Myocardial Infarction (TIMI) major non-coronary artery bypass graft bleeding events were infrequent and not different between the two therapies (P=0.96 and 0.38, respectively). In PLATO, treatment with ticagrelor compared with clopidogrel resulted in a reduction in total events, including first and subsequent recurrent cardiovascular events, when compared with clopidogrel. These types of analyses demonstrate an even greater absolute benefit of ticagrelor over clopidogrel than previously reported. URL: http://www.clinicaltrials.gov/. Unique identifier: NCT00391872.

Pharmacotherapeutic Considerations for the Use of Prasugrel and Ticagrelor to Reduce Stent Thrombosis in Patients With Acute Coronary Syndrome

Despite the improvement in stent technology, stent thrombosis (ST), a potentially catastrophic event, still occurs. Among several risk factors for ST, high on-treatment platelet reactivity to clopidogrel has been demonstrated to play a role, occurring in about one-third of the patients. In order to overcome this limitation, prasugrel and ticagrelor, newer P2Y12 inhibitors, have been developed and approved for clinical use. Two large clinical trials, TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel-thrombolysis in myocardial infarction (TRITON-TIMI) 38 and Study of Platelet Inhibition and Patient Outcomes (PLATO), evaluated these drugs in patients with acute coronary syndrome (ACS), showing a significant improvement in efficacy end points (including a prominent reduction in ST occurrence) compared to clopidogrel. In contrast, the TRILOGY ACS trial found no benefit with prasugrel compared to clopidogrel in patients with medically treated ACS. The aim of this review is to consider decision-making strategies between prasugrel and ticagrelor in daily clinical practice.

Outcome and causes of renal deterioration evaluated by serial cystatin C measurements in acute coronary syndrome patients—Results from the PLATelet inhibition and patient Outcomes (PLATO) study

To investigate if ticagrelor treatment and other clinical characteristics were associated with increased cystatin C concentrations and if a deterioration in estimated renal function was associated with worse outcome in patients with acute coronary syndromes (ACS). Plasma cystatin C concentrations were determined within 24 hours of admission (baseline), at discharge, 1 month, and 6 months in the PLATO trial. The changes over time in relation to randomized treatment were analyzed by analysis of covariance. C-statistics and the relative Integrated Discrimination Improvement of the cystatin C concentrations regarding the primary outcome (cardiovascular death or myocardial infarction) was evaluated by multivariable analysis including background characteristics and biomarkers: N-terminal-pro-B-type natriuretic peptide and Troponin I. Mean cystatin C concentrations in 2133 ticagrelor- and 2162 clopidogrel-treated patients were at baseline (0.86 mg/L and 0.86 mg/L), discharge (1.01 mg/L and 0.98 mg/L) (P < .0005), 1 month (1.00 mg/L and 0.98 mg/L) (P = .12), and 6 months (1.00 mg/L and 0.99 mg/L) (P = .17), respectively. Age, heart failure, and type of ACS were major determinants of the cystatin C concentration. c Statistics and the relative Integrated Discrimination Improvement of the primary outcome for the baseline cystatin C concentration were 0.687 and 5.2%, compared to 0.684 and 4.5% at discharge (n = 4034) and 0.693 and 5.1% at one month (n = 3096), respectively. Mean cystatin C concentrations increased in ACS patients, most importantly determined by age. The initial greater increase in ticagrelor-treated patients was not sustained over time. Risk prediction did not improve with serial measurements of renal markers.

Angiotensin Receptor Blockers Worsen Renal Function and Dyspnea on Ticagrelor: A Potential Ticagrelor‐Angiotensin Receptor Blocker Interaction?

Ticagrelor is a new antiplatelet agent that was pitted against clopidogrel in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Because ticagrelor is the first oral, reversible, twice-daily agent, sufficient information on drug interactions is not available. Our objective was to ascertain the safety of ticagrelor with other common medications. The US Food and Drug Administration Complete Response Review indicates that renal adverse events (AEs) and renal function AEs were higher in ticagrelor-treated patients who were concomitantly treated with angiotensin receptor blockers (ARBs) >50% of study days compared to ticagrelor-treated patients who did not receive ARBs >50% of study days. Clopidogrel-treated patients showed a trend for an increase in adverse renal events with ARB use. However, this was not as pronounced as that observed with ticagrelor. Dyspnea was also significantly increased in patients on concomitant ticagrelor-ARB compared to ticagrelor without concomitant ARB and clopidogrel (21.4% vs 14.6% vs 9.9%, respectively) as well as angioedema (0.15% vs 0.09%). Furthermore, in patients with a baseline estimated glomerular filtration rate (eGFR) <30 mL/min, the risk of major bleeding, death, and renal failure was increased in patients on ticagrelor compared to patients on clopidogrel. In patients on ticagrelor, ARBs significantly increased the frequency of renal related AEs, renal function AEs, and dyspnea. Moreover, in patients with a baseline eGFR <30 mL/min, the risk of major bleeding, death, and renal failure was increased in patients on ticagrelor compared to patients on clopidogrel.

Factors Contributing to the Lower Mortality With Ticagrelor Compared With Clopidogrel in Patients Undergoing Coronary Artery Bypass Surgery

This study investigated the differences in specific causes of post-coronary artery bypass graft surgery (CABG) deaths in the PLATO (Platelet Inhibition and Patient Outcomes) trial. In the PLATO trial, patients assigned to ticagrelor compared with clopidogrel and who underwent CABG had significantly lower total and cardiovascular mortality. In the 1,261 patients with CABG performed within 7 days after stopping study drug, reviewers blinded to treatment assignment classified causes of death into subcategories of vascular and nonvascular, and specifically identified bleeding or infection events that either caused or subsequently contributed to death. Numerically more vascular deaths occurred in the clopidogrel versus the ticagrelor group related to myocardial infarction (14 vs. 10), heart failure (9 vs. 6), arrhythmia or sudden death (9 vs. 3), and bleeding, including hemorrhagic stroke (7 vs. 2). Clopidogrel was also associated with an excess of nonvascular deaths related to infection (8 vs. 2). Among factors directly causing or contributing to death, bleeding and infections were more common in the clopidogrel group compared with the ticagrelor group (infections: 16 vs. 6, p < 0.05, and bleeding: 27 vs. 9, p < 0.01, for clopidogrel and ticagrelor, respectively). The mortality reduction with ticagrelor versus clopidogrel following CABG in the PLATO trial was associated with fewer deaths from cardiovascular, bleeding, and infection complications. (Platelet Inhibition and Patient Outcomes [PLATO]; NCT00391872).

Letter by Fort and Plachetka Regarding Article, “Association of Proton Pump Inhibitor Use on Cardiovascular Outcomes With Clopidogrel and Ticagrelor: Insights From PLATO”

To the Editor: We agree with Goodman et al1 regarding their interpretation of the Platelet Inhibition and Patient Outcomes (PLATO) trial data that the use of proton pump inhibitors (PPIs) and other gastroprotective drugs is a marker for patients at higher risk for subsequent cardiovascular (CV) or gastrointestinal events. Although the authors correctly assessed baseline characteristics and other markers that could provide a rationale for this increased risk, there potentially is another explanation for the …

Ticagrelor Versus Clopidogrel in Elderly Patients With Acute Coronary Syndromes

Elderly patients with acute coronary syndrome are at high risk of recurrent ischemic events and death, and for both antithrombotic therapy and catheter-based complications. This prespecified analysis investigates the effect and treatment-related complications of ticagrelor versus clopidogrel in elderly patients (≥75 years of age) with acute coronary syndrome compared with those <75 years of age. The association between age and the primary composite outcome, as well as major bleeding were evaluated in the PLATelet inhibition and patient Outcomes (PLATO) trial using Cox proportional hazards. Similar models were used to evaluate the interaction of age with treatment effects. Hazard ratios were adjusted for baseline characteristics. The clinical benefit of ticagrelor over clopidogrel was not significantly different between patients aged ≥75 years of age (n=2878) and those <75 years of age (n=15 744) with respect to the composite of cardiovascular death, myocardial infarction, or stroke (interaction P=0.56), myocardial infarction (P=0.33), cardiovascular death (P=0.47), definite stent thrombosis (P=0.81), or all-cause mortality (P=0.76). No increase in PLATO-defined overall major bleeding with ticagrelor versus clopidogrel was observed in patients aged ≥75 years (hazard ratio, 1.02; 95% confidence interval, 0.82-1.27) or patients aged <75 years (hazard ratio, 1.04; 95% confidence interval, 0.94-1.15). Dyspnea and ventricular pauses were more common during ticagrelor than clopidogrel treatment, with no evidence of an age-by-treatment interaction. The significant clinical benefit and overall safety of ticagrelor compared with clopidogrel in acute coronary syndrome patients in the PLATO cohort were not found to depend on age.

Circulation Editors' Picks

<i>Circulation</i> Editors' Picks

Prior smoking status, clinical outcomes, and the comparison of ticagrelor with clopidogrel in acute coronary syndromes—Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial

Habitual smoking has been associated with increased platelet reactivity, increased risk of thrombotic complications and greater efficacy of clopidogrel therapy over placebo. In the PLATO trial, ticagrelor compared to clopidogrel in patients with acute coronary syndromes (ACS) reduced the primary composite end point of vascular death, myocardial infarction and stroke, without increasing overall rates of major bleeding. We evaluated the results in relation to smoking habits. Interactions between habitual smokers (n = 6678) and in ex/nonsmokers (n = 11,932) and the effects of randomized treatments on ischemic and bleeding outcomes were evaluated by Cox regression analyses. Habitual smokers had an overall lower risk profile and more often ST-elevation ACS. After adjustment for baseline imbalances, habitual smoking was associated with a higher incidence of definite stent thrombosis (adjusted HR, 1.44 [95% CI, 1.07-1.94]); there were no significant associations with other ischemic or bleeding end points. The effects of ticagrelor compared to clopidogrel were consistent for all outcomes regardless of smoking status. Thus, there was a similar reduction in the primary composite end point for habitual smokers (adjusted HR, 0.83 [95% CI, 0.68-1.00]) and ex/nonsmokers (adjusted HR, 0.89 [95% CI, 0.79-1.00]) (interaction P = .50), and in definite stent thrombosis for habitual smokers (adjusted HR, 0.59 [0.39-0.91]) and ex/nonsmokers (adjusted HR, 0.69 [95% CI, 0.45-1.07]) (interaction P = .61). In patients hospitalized with ACS, habitual smoking is associated with a greater risk of subsequent stent thrombosis. The reduction of vascular death, myocardial infarction, stroke, and stent thrombosis by ticagrelor compared to clopidogrel is consistent regardless of smoking habits.

How country-specific should a country-specific cost-effectiveness analysis be?

This editorial refers to ‘Cost-effectiveness of dabigatran compared with warfarin for patients with atrial fibrillation in Sweden’†, by T. Davidson et al. , on page 177 and ‘Cost-effectiveness of treating acute coronary syndrome patients with ticagrelor for 12 months: results from the PLATO study’‡, by E. Nikolic et al. , on page 220 Two recent cost-effectiveness analyses published in the European Heart Journal add to a growing evidence base regarding the costs and health outcomes associated with dabigatran vs. warfarin for patients with atrial fibrillation1 and ticagrelor vs. clopidogrel for patients with acute coronary syndromes.2 Conducted from the perspective of the Swedish healthcare system, both analyses are trial-based economic evaluations augmented with decision models to extrapolate short-term trial outcomes to longer term estimates of costs and quality-adjusted survival. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) provided primary data for the cost-effectiveness analysis of dabigatran vs. warfarin.3 The Platelet Inhibition and Patient Outcomes (PLATO) trial provided primary data for the cost-effectiveness analysis of ticagrelor vs. clopidogrel.4 Both trials were large, multinational, randomized controlled studies. RE-LY enrolled 18 113 patients in 44 countries, and PLATO enrolled 18 624 patients in 43 countries. In both analyses, the analysts relied on clinical data that were pooled across all countries represented in the trial. To inform decision making in Sweden, …

Rapid P2Y 12 Inhibition

Acute coronary syndrome (ACS) is still a serious condition associated with decreased quality of life, increased healthcare expenditures, and premature death. The prevalence of ACS is expected to increase with aging of the population and with the epidemics of obesity and diabetes. The short- and long-term mortality after an ACS has been dramatically reduced by the development of revascularization techniques and new antithrombotic agents. The past decade has seen many trials evaluating new oral and parenteral antiplatelet agents with greater potency than aspirin and clopidogrel. Several antiplatelet agents have been developed, with the ultimate goal to obtain optimal antiplatelet therapy for both the acute and the chronic phases of disease. Articles see p 336, 347 Ideally, efficiency requires several pharmacodynamic proprieties, such as a fast onset of action (immediate onset for emergency situations), a strong degree of platelet inhibition (at least stronger than the standard of care [aspirin and clopidogrel]), a narrow interindividual variability with no impact of genetic variants and no drug-to-drug interaction, and an easy administration (an oral drug for maintenance therapy and an intravenous formulation for rapid loading). Of course, this drug should also lead to a convincing reduction of recurrent ischemic events in an adequately powered phase 3 trial. With regard to safety, the illusion of having the same dose of a single antiplatelet drug to treat all clinical situations has passed. The degree of platelet activation and aggregation is different across clinical situations (eg, acute ST-segment–elevation myocardial infarction [STEMI] versus secondary prevention) and varies over time in the same patient. Recent large phase 3 trials have confirmed the importance of dosing and the target population treated with the new agents.1–4 From a safety standpoint, an ideal antiplatelet agent would also have an intravenous and oral formulation, with different doses tested in …

Ticagrelor vs. Clopidogrel in PLATO Patients with Prior Stroke or Transient Ischemic Attack

In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor — an oral, nonthienopyridine P2Y12 inhibitor — was superior to clopidogrel

Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and a History of Stroke or Transient Ischemic Attack

Patients with acute coronary syndromes and history of stroke or transient ischemic attack (TIA) have an increased rate of recurrent cardiac events and intracranial hemorrhages. We evaluated treatment effects of ticagrelor versus clopidogrel in patients with acute coronary syndrome with and without a history of prior stroke or TIA in the PLATelet inhibition and patient Outcomes (PLATO) trial. Of the 18 624 randomized patients, 1152 (6.2%) had a history of stroke or TIA. Such patients had higher rates of myocardial infarction (11.5% versus 6.0%), death (10.5% versus 4.9%), stroke (3.4% versus 1.2%), and intracranial bleeding (0.8% versus 0.2%) than patients without prior stroke or TIA. Among patients with a history of stroke or TIA, the reduction of the primary composite outcome and total mortality at 1 year with ticagrelor versus clopidogrel was consistent with the overall trial results: 19.0% versus 20.8% (hazard ratio, 0.87; 95% confidence interval, 0.66-1.13; interaction P=0.84) and 7.9% versus 13.0% (hazard ratio, 0.62; 95% confidence interval, 0.42-0.91). The overall PLATO-defined bleeding rates were similar: 14.6% versus 14.9% (hazard ratio, 0.99; 95% confidence interval, 0.71-1.37), and intracranial bleeding occurred infrequently (4 versus 4 cases, respectively). Patients with acute coronary syndrome with a prior history of ischemic stroke or TIA had higher rates of clinical outcomes than patients without prior stroke or TIA. However, the efficacy and bleeding results of ticagrelor in these high-risk patients were consistent with the overall trial population, with a favorable clinical net benefit and associated impact on mortality. URL: http://www.clinicatrials.gov. Unique identifier: NCT00391872.

Ticagrelor in ST-Elevation Myocardial Infarction

Ticagrelor is a new oral antagonist of the platelet P2Y₁₂ receptor that offers several potential advantages compared to clopidogrel including faster and more effective inhibition of platelet aggregation. Ticagrelor has been compared to clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) trial in a broad population of patients with acute coronary syndrome showing a reduction of the 12-month risk of death from vascular causes, myocardial infarction and stroke without increasing the overall risk of major bleeding. In a subanalysis of the PLATO trial focusing on patients with ST-elevation myocardial infarction, ticagrelor results were consistent with those of the overall trial. Additionally, possible pleiotropic effects of ticagrelor, including an appealing interaction with adenosine, might constitute a specific advantage in this particular subset of patients.

Cardiovascular Pharmacogenomics: Current Status and Future Directions—Report of a National Heart, Lung, and Blood Institute Working Group

The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group on January 7, 2011, at George Washington University in Washington, DC, to provide recommendations to the NHLBI that would guide informed decisions on research directions and priorities in the field of cardiovascular