Reports

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MEDICAL FRONTIERS - 31st Annual Congress of the European Society of Cardiology

Barcelona, Spain / August 29-September 2, 2009

More effective antiplatelet regimens to prevent thrombotic events in patients with acute coronary syndrome (ACS) are being defined on the basis of recently completed multinational studies. Of new data, the most important appears to be the phase III trial of the investigational drug ticagrelor. The results were considered to be a breakthrough because the reduction in thrombotic events relative to a standard regimen of clopidogrel was achieved in the absence of any significant increase in the risk of major bleeding. In addition, the compound yielded a relative mortality benefit.

“Before this trial, we did not think that it was possible to get more antiplatelet effect without also producing unacceptable rates of bleeding. This study has changed that concept,” stated the senior author of the ticagrelor study, Dr. Lars Wallentin, Uppsala Clinical Research Center, Sweden. In summarizing the trial, called PLATO (Platelet inhibition And Treatment Outcomes), the lead investigator emphasized that “over the last 10 to 15 years, we have not seen any other trial with an antithrombotic compound that lowered total mortality.”

PLATO

In the PLATO study, 18,624 patients hospitalized with ACS with or without ST-segment elevation were randomized to ticagrelor or clopidogrel. Both agents inhibit the P2Y12, a surface receptor critical to platelet activation. The novel compound was administered in a 180-mg loading dose followed by a maintenance dose of 90 mg b.i.d. The clopidogrel group received 300 or 600 mg of clopidogrel at the discretion of the physician followed by a maintenance regimen of 75 mg/day. Both compounds were given on top of ASA. The primary composite end point was death from vascular causes, myocardial infarction (MI) or stroke. The primary safety end point was major bleeding.

At the end of 12 months of follow-up, ticagrelor was associated with a 16% reduction in the primary composite end point relative to clopidogrel (HR 0.84; 95% CI, 0.77-0.92; P<0.001) (Figure 1). Unlike previous studies comparing a more effective antiplatelet drug to another, this relative advantage was not associated with any significant differences in the rate of major bleeding (11.6% vs. 11.2%, respectively; P=0.43). When each of the components of the primary outcome, which were predefined as secondary end points, were evaluated separately, there was a significant advantage relative to clopidogrel for all except stroke (1.5% vs. 1.3%; P=0.22).

Figure 1.

The relative mortality benefit is perhaps the most compelling feature of the study because the protection was achieved against an active, standard-of-care regimen. Relative to clopidogrel, the 1.1% absolute advantage at 12 months for mortality for vascular causes (4.0% vs. 5.1%) translated into a relative protection of 21% (HR 0.79; 95% CI, 0.69-0.91; P<0.001). The absolute difference for death from any cause was of the same magnitude (4.5% vs. 5.9%), producing a 22% relative risk reduction (HR 0.78; 95% CI, 0.69-0.89; P<0.001).

The greater efficacy of ticagrelor was anticipated on the basis of earlier clinical and experimental studies that associated this agent with faster, greater and more consistent inhibition of P2Y12 than clopidogrel. Another agent that works along this same pathway, prasugrel, has also demonstrated more consistent and greater antiplatelet effects than clopidogrel in an earlier comparative trial called TRITON-TIMI 38 (TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet iNhibition with prasugrel — Thrombolysis In Myocardial Infarction). However, the reduction in clinical events on prasugrel relative to clopidogrel was associated with a 32% relative increase in major bleeding (HR 1.32; 95% CI, 1.03-1.68; P=0.03) that included an increase in fatal bleeding (0.4% vs. 0.1%; P=0.002) (Wiviott et al. N Engl J Med 2007; 357:2001-2015).

In PLATO, there was no difference in major bleeding either by the prespecified definition or by the definition developed by TIMI trial investigators. The lack of a significant difference on the primary measure of bleeding was reinforced by many secondary safety end points, such as a lack of significant difference in fatal or life-threatening bleeding. There was a greater rate of bleeding unrelated to coronary artery bypass graft (CABG) (4.5% vs. 3.8%; P=0.03) and major or minor bleeding combined (16.1% vs. 14.6%; P=0.008) on ticagrelor, but clopidogrel was associated with a higher rate of fatal non-intracranial bleeding (0.1% vs. 0.3%; P=0.03). The rates of fatal intracranial bleeding were very low in both groups (<0.02% vs. <0.01%) but higher on ticagrelor (P=0.02).

The only other adverse events differentiating the two treatments were dyspnea and benign tumours. Dyspnea occurred in 13.8% of the ticagrelor group and 7.8% of the clopidogrel group (P<0.001), but discontinuations for dyspnea occurred in less than 1% of either group (0.9% vs. 0.1%; P<0.001). Benign tumours occurred in 0.4% of the clopidogrel group and 0.2% of the ticagrelor group (P=0.02), but the low rates and marginal significance suggest that this may be a spurious finding. At 12 months, there was a greater increase in serum creatinine (11% vs. 9%; P<0.001) and serum uric acid (15% vs. 7%; P<0.001) on ticagrelor, but the increases were reversible on either therapy with discontinuation. A Holter monitoring substudy did not reveal any significant differences in risk of ventricular pauses between therapies at 30 days.

There were other notable outcomes that were consistent with the greater antiplatelet activity of ticagrelor relative to clopidogrel. Most important of these was the reduction in stent thrombosis. Almost two-thirds of the randomized patients (11,289) received a stent. Whether stratified as definite thrombosis (1.3% vs. 1.9%; P=0.009), definite or probable thrombosis (2.2% vs. 2.9%; P=0.02) or definite, probable or possible thrombosis (2.9 vs. 3.8%; P=0.01), there was a significant advantage for the novel agent.

Based on the data generated by the study, Dr. Wallentin calculated that administering ticagrelor rather than clopidogrel in 1000 patients would result in 14 fewer deaths, 11 fewer MIs, six to eight fewer stent thromboses and no increase in major bleeds. Nine patients started on ticagrelor would need to be switched to clopidogrel due to dyspnea.

Dr. Wallentin told delegates, “Ticagrelor is more effective than clopidogrel for continuing prevention of ischemic events for acute and long-term therapy in patients with ACS.” He characterized the reduction in mortality as one of the largest ever achieved in a comparison of two active therapies in cardiovascular disease, and he anticipates an important role for the new compound when it becomes clinically available.

CURRENT OASIS 7

The second study, called CURRENT OASIS 7 (Clopidogrel optimal loading dose Usage to Reduce RecurrENT events/Optimal Antiplatelet Strategy for InterventionS), also indicates that antiplatelet potency is not necessarily inseparable from risk of bleeding. In this trial, 25,087 ACS patients scheduled for early PCI were randomized by two factors. The first was the dose of clopidogrel (600-mg loading dose followed by 150-mg maintenance dose vs. 300-mg loading dose followed by 75-mg maintenance dose) and the second was the dose of ASA (300 to 325 mg vs. 75 to 100 mg). The primary end point was the same composite of events used in PLATO: cardiovascular death, MI or stroke. Major bleeding was the primary safety measure.

For the primary end point, the 0.2% absolute reduction in events on the high dose vs. the standard dose of clopidogrel only translated into a non-significant 5% relative risk reduction (HR 0.95; 95% CI, 0.84-1.07; P=NS). However, the 7855 (31%) patients who never proceeded to a PCI in this study were far higher than expected. When these patients were removed from the analysis, there was a 15% relative risk reduction (HR 0.85; 95% CI, 0.74-0.99; P<0.01) in the primary end point driven largely by the 22% reduction in MI (HR 0.78; 95% CI, 0.64-0.95; P<0.01). In addition, PCI patients on the high dose of clopidogrel achieved a 42% relative reduction in the risk of definite stent thrombosis (HR 0.58; 95% CI, 0.42-0.79; P=0.001). As in PLATO, there was no significant difference in major bleeding (0.5% in both groups). Although there was an almost 50% increase in blood transfusions of more than 2 units (HR 1.49; 95% CI, 1.11-1.98; P<0.01) in those receiving the high dose, fatal bleeds were numerically although non-significantly lower (0.07% vs. 0.15%; P=NS).

These findings, despite the lack of benefit on the prespecified primary outcome in the total study population, are considered important and relevant because the PCI group was the target of the study. Even when non-PCI patients are excluded from the analysis, the remaining population constitutes one of the largest ACS studies ever conducted. Senior author Dr. Shamir Mehta, Associate Professor of Medicine (Cardiology), McMaster University, Hamilton, Ontario, suggested that the findings would change practice.

The results “will likely get recognition from guideline committees in some way,” he observed, emphasizing that the higher dose of clopidogrel reduced clinical risks with no cost in major bleeds. He indicated that there is a large gain from a relatively minor change in practice.“It is a simple change to institute. It’s going from one pill to two pills a day [of clopidogrel]. The cost implications are virtually negligible, and the benefits are large. This simple manoeuvre could improve patient outcomes in PCI patients.”

In contrast, the CURRENT OASIS 7 trial did not associate the higher dose of ASA with any greater benefit in the study population overall, in those who never underwent PCI or in those who did undergo PCI. In the overall study population, the 0.2% absolute risk reduction (4.2% vs. 4.4%) on the higher ASA dose translated into a non-significant 4% relative reduction (HR 0.96; 95% CI, 0.85-1.08; P=NS). The results were similar in the PCI and non-PCI subgroups. Major bleeding also did not rise with increased doses of ASA, but the results overall are consistent with other evidence that any additional antiplatelet effect at doses over 100 mg is relatively modest.

However, the equivocal results do not completely resolve the controversy about whether all patients should be given low-dose ASA, a more common practice in Europe than in North America. Although there were no significant differences, Dr. Mehta noted that the higher dose was consistently favoured on major outcomes even if the differences were insignificant. Although the data do not prove an advantage, “there was no downside.” Ultimately, the data suggest that either dose of ASA is acceptable.

The Role of PPIs

In a third study of immediate importance of the use of antiplatelet therapy in ACS management, a retrospective but detailed analysis of patients receiving P2Y12 inhibitors in large clinical trials failed to find any significant interaction with concomitant proton pump inhibitor (PPI) therapy. The study combined data from the 13,608 patients in TRITON-TIMI 38 and the smaller 201-patient PRINCIPLE-TIMI 44 (Prasugrel compared with high-loading and maintenance-dose clopidogrel in patients with planned PCI: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction). Addressing an important controversy raised in an observational analysis almost two years ago, the new analysis did not find any significant differences in outcome when those on PPI, representing about one-third of patients evaluated, were compared to those who were not. This was true for both clopidogrel and prasugrel.

“These data can provide some early reassurance to clinicians that these two classes of drugs may in fact be safe to use in combination for patients who have a strong indication to be on both drugs,” reported the senior author Dr. Michelle L. O’Donoghue, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. Although she cautioned that a randomized prospective trial is needed for definitive evidence, this may be the best evidence currently available.

Agreeing with this characterization, Dr. Kurt Huber, Department of Cardiology, Wilhelminen Hospital, Vienna, Austria, suggested the strength of this analysis is that it was drawn from a well-defined population with relatively good information on PPI exposure. Although he, too, said that definitive results should be based on a prospective study randomizing patients for PPI use, these findings provide support for current guidelines that endorse PPI use in patients on antiplatelet therapy when there are good indications for both.

Summary

The evidence that greater antithrombotic activity can be achieved with more potent antiplatelet drugs without significantly increasing risk of major bleeding confirms progress in reducing risk of vascular events in patients with ACS. The results of the PLATO study are considered to be particularly important because they associate the study drug with an all-cause mortality benefit, an outcome difficult to achieve in trials comparing two different active therapies. In addition, the evidence that greater risk reductions can be achieved in PCI patients by simply doubling the loading and maintenance dose of clopidogrel has provided an immediate potential step in improved patient management, while the absence of an effect of PPI therapy on antiplatelet effect is reassuring in a population for which PPI use is common.

Note: At press time, ticagrelor is not available in Canada.