Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - 59th Annual Scientific Session of the American College of Cardiology (ACC)

Atlanta, Georgia / March 14-16, 2010

The data generated by recent phase III, multinational trials directly comparing the newer antiplatelet agents ticagrelor and prasugrel with clopidogrel, the long-time standard, demonstrate that greater protection against vascular events can be achieved with greater antiplatelet effect. The large reductions in the primary composite end point of death from cardiovascular (CV) causes, nonfatal myocardial infarction (MI) and nonfatal stroke for both agents relative to clopidogrel indicate that the potency of antiplatelet therapies can be increased. However, important considerations should be made for the potential increased risk of bleeding events in certain patients.

In PLATO (Study of Platelet Inhibition and Patient Outcomes), the reduction in the composite end point for ticagrelor relative to clopidogrel was 16% (HR 0.84; 95% CI, 0.77-0.92; P<0.001) in patients admitted to hospital with acute coronary syndrome (ACS) whether or not they had an ST-segment elevation. In TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38), this composite end point was reduced 19% (HR 0.81; 95% CI, 0.73-0.90; P<0.001) on prasugrel treatment relative to clopidogrel in patients hospitalized with ACS and scheduled for a percutaneous intervention (PCI). The greater efficacy in both cases is consistent with a large body of experimental evidence demonstrating that these newer agents work more quickly and more effectively.

According to Dr. Jeffrey Anderson, University of Utah School of Medicine, Salt Lake City, “There is likely to still be a role for clopidogrel in selected patients so I do not think that this agent will be abandoned, but these large studies demonstrate that it is not the most effective antiplatelet agent for reducing vascular events in an ACS population even when used in higher doses.”

A similar assessment was made by Dr. Deepak Bhatt, Director, Integrated Interventional Cardiovascular Program, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. He noted that in TRITON-TIMI 38, the 2.2% absolute risk reduction (P<0.001) with prasugrel relative to clopidogrel in the primary composite end point of major vascular events exceeded the 0.3% absolute increase (P=0.002) in fatal bleeding. In PLATO, there was no significant difference between ticagrelor and clopidogrel for rates of major bleeding. In addition, ticagrelor was associated with a reduction in all-cause mortality, a secondary end point.

“All-cause mortality reductions are difficult to achieve, and they provide a very strong absolute indication that one therapy is better than another for the most important outcome, which is survival,” Dr. Bhatt told delegates. Although he agreed that a choice of agents might be useful for individualizing antiplatelet therapy, he, like others, placed particular emphasis on the relative safety of ticagrelor in relationship to bleeding, which is likely to have played a role in the ability of this agent to show a mortality advantage.

The 22% relative reduction in all-cause mortality (HR 0.78; 95% CI, 0.69-0.89; P<0.001) seen in PLATO was highly significant. However, new data demonstrate that it was well distributed among important subpopulations of the 18,624 patients who participated in the study, which was initially published more than six months ago (Wallentin et al. N Engl J Med 2009;361:1045-57).

Study Implications

In a recently completed retrospective analysis on the 1899 PLATO patients who underwent coronary artery bypass grafting (CABG), post-randomization showed a 16% relative risk reduction in the ticagrelor-treated patients compared to clopidogrel patients (HR 0.84; 95% CI, 0.60-1.16; P=0.29). The subgroups were not powered to show a statistical difference in the primary composite end point; however, there was a highly significant mortality advantage for ticagrelor in this population. This included a 51% (HR 0.49; 95% CI, 0.32-0.77; P<0.01) reduction in death from any cause and a 46.6% (P<0.01) reduction in CV mortality (Figure 1). As in the overall PLATO results, there was no significant difference in CABG-related major bleeding between the treatment arms.

In PLATO, patients were randomized to loading doses of ticagrelor (180 mg) or clopidogrel (300 mg) at the time of hospitalization but patients who received pre-admission clopidogrel (either as a maintenance antiplatelet agent or as an acute loading dose administered by emergency responders) were not excluded from the study. This resulted in a sizeable proportion of the patients in the clopidogrel arm receiving 600 mg on the day of admission. Clopidogrel maintenance was 75 mg/day. After the loading dose, ticagrelor patients received 90 mg maintenance twice daily. In the subgroup of patients scheduled for CABG after admission, for which a new analysis was presented by Dr. Claes Held, Uppsala Clinical Research Centre, Uppsala University, Sweden, the recommended protocol was to stop ticagrelor 24 to 72 hours before surgery and clopidogrel 5 days prior to surgery. All patients underwent CABG within 7 days after their last dose of study drug.

Figure 1.

These CABG results help validate one of the features of ticagrelor which—unlike either clopidogrel or prasugrel—is a reversible agent. While all three of these agents exert an antiplatelet effect by inhibiting the P2Y12 receptor, both ticagrelor and prasugrel act more quickly and with greater potency, so that peak effects are achieved more rapidly. However, unlike clopidogrel or prasugrel, which are irreversibly bound, ticagrelor comes off the receptor at the end of its pharmacologic activity, restoring platelet function. ACS patients who are likely to require CABG are among those for whom reversibility is an advantage because of the opportunity to more favourably time the return of platelet activity. This reversibility likely explains why the rates of major bleeding in the CABG subpopulation were non-significantly lower (7.4% vs. 7.9%; P=0.32), even though the protection from events was greater.

Bleeding, All-cause Mortality

In the TRITON-TIMI 38 study published more than two years ago (Wiviott et al. N Engl J Med 2007;357:2001-15), the reduction in total mortality on prasugrel relative to clopidogrel did not reach statistical significance (3.0% vs. 3.2%; P=0.64), but mortality reductions were observed in subgroups that derived the greatest relative benefit from prasugrel, such as patients with diabetes (1.8% vs. 3.8%; P<0.0001). Conversely, there were some patient groups for whom there was no relative advantage and a potential for harm for prasugrel over clopidogrel because the increase in the risk of bleeding exceeded the relative risk reduction for vascular events. These included patients older than 75, patients who weighed less than 60 kg and patients with a history of stroke or a transient ischemic attack. It is the range of benefit-to-risk among patients in the TRITON-TIMI 38 trial that has led to calls for individualization of therapy once these newer, more potent antiplatelet agents become available.

In PLATO, the risk of major bleeding overall and among several evaluated subgroups, including those defined by age and weight, were similar in the ticagrelor and clopidogrel groups. In a detailed analysis of all forms of major bleeding, the only difference for which events were significantly more common with ticagrelor than clopidogrel involved non-CABG episodes (4.5% vs. 3.8%; P=0.03).

“There are clearly patients who can benefit from greater antiplatelet effect, and in these patients we have a potential to substantially reduce the risk of vascular events with these newer agents,” reported Dr. Marc Sabatine, Brigham and Women’s Hospital.

Dyspnea and Ventricular Pauses

While ticagrelor was well tolerated in PLATO, the two safety concerns that emerged from the data were dyspnea (13.8% vs. 7.8%; P<0.001) and ventricular pauses of at least 3 seconds on Holter monitoring (5.8% vs. 3.6%; P=0.01). Both have been the focus of new analyses to gauge their clinical significance. In one, a substudy of pulmonary function was conducted in 199 PLATO patients. The patients were evaluated with pulse oximetry, spirometry, lung volumes and diffusion capacity. Tests were performed on study medication and then 20 to 30 days after the antiplatelet agents were discontinued. The study was unable to find any difference in pulmonary function between the two groups at any timepoint.

“These data suggest that the dyspnea is not the result of a change in lung function on ticagrelor but some transient effect,” reported Dr. Robert F. Storey, University of Sheffield, UK. He noted that in the overall results of PLATO, less than 1% (0.9%) discontinued ticagrelor for dyspnea even though more than 10% (13.8%) had at least one episode. Asked to speculate on the cause, Dr. Storey suggested, “We think that it relates to the activity on adenosine. Ticagrelor inhibits uptake of adenosine which is involved in lung reactivity, although this has not yet been proven as a cause of the dyspnea observed.” The same mechanism of action is suspected in the greater rate of ventricular pauses in PLATO. In another PLATO substudy that evaluated 2908 patients with continuous electrocardiogram monitoring over 7 days, there was a higher number of ventricular pauses lasting at least 3 seconds in the ticagrelor group, but the difference between the two groups was most pronounced and only statistically significant at randomization. By day 30, the slightly higher rate in the ticagrelor group was no longer significant, although these ventricular pauses were significantly more common in patients with more than 4 pauses over any eight-hour period during night-time hours (but not during day or
e 2).

Figure 2.

<img3916|center>

“Most pauses [66%] were sinoatrial nodal and most were asymptomatic,” reported Dr. Benjamin M. Scirica, Brigham and Women’s Hospital. Reiterating that the most likely explanation is transient blockade of adenosine uptake, Dr. Scirica added, “We did not observe any clinical consequences related to the excess of these pauses, so the importance even among patients with a known arrhythmia is uncertain.”

Faster Onset, Greater Potency

The greater efficacy of newer antiplatelet agents is consistent with a series of preclinical and clinical studies demonstrating a much faster onset of action and a greater peak antiplatelet effect on either prasugrel or ticagrelor.

In a crossover study in healthy volunteers, the inhibition of platelet aggregation on prasugrel was superior to clopidogrel within 15 minutes of drug ingestion (P<0.01), and it remained significantly greater over the full 24 hours of evaluation (Brandt et al. Am Heart J 2007;153:(66):e9-e16.). In the ONSET-OFFSET study, the greater antiplatelet effect of ticagrelor relative to clopidogrel was already highly significant within 30 minutes (P<0.0001) and retained this relative superiority at all timepoints through 24 hours (Gurbel et al. Circulation 2009;120:2577-85). At two hours, 98% of ticagrelor patients vs. 31% of clopidogrel patients (P<0.0001) had achieved at least a 50% inhibition of platelets.

However, reflecting the reversibility of ticagrelor, the offset was also greater. By 72 hours, ticagrelor was no longer exerting a substantial antiplatelet effect, producing an antiplatelet activity that was similar to clopidogrel after it had been discontinued for five days.

Testing for Clopidogrel Resistance and Other Developments

The high potency of both ticagrelor and prasugrel may not fully explain the difference in clinical activity. Due to interindividual variability of response and resistance, about 25% of clopidogrel patients do not fully achieve the predicted antiplatelet effect. Some of this resistance can be overcome by increasing the dose, leading many centres to employ 600 mg of clopidogrel as a loading dose followed by up to 150 mg of a maintenance therapy. However, several experts have proposed routine testing of platelet inhibition in patients starting clopidogrel in order to rapidly identify poor or non-responders so that other antiplatelet strategies can be substituted.

“The problem with routine testing of clopidogrel resistance is that many institutions are not going to want to set up a protocol in an urgent care situation, such as patients being admitted for ACS,” cautioned faculty member of the University of Florida College of Medicine Dr. Dominick Angiolillo, who practices in Jacksonville, Florida. He suggested that the newer antiplatelet agents might be a better solution, not only because their activity is more consistent but because they act more rapidly and are more potent.

Since the original warning in 2008 that proton pump inhibitors (PPIs) might interact with antiplatelet therapy, various contradicting reports have surfaced. Further confirmation of these reports was again presented here in an observational study of PCI patients who had undergone PCI for stable or unstable CAD. Cardiologist Dr. Kishore Harjai, Guthrie Health System, Sayre, Pennsylvania, and colleagues studied 2646 patients who were divided into PPI (n=771) or non-PPI (n=1875) groups, depending on whether or not they were given a PPI at discharge. Study outcomes included death, MI, death or MI, ST-segment elevation, target vessel revascularization and major adverse cardiac events. Results indicated that PPI use did not affect any study outcomes and that both groups had similar clinical outcomes, regardless of whether or not they had received a PPI after PCI.

Summary

Two new antiplatelet agents have demonstrated greater protection against major vascular events in patients with ACS. The greater efficacy in the blinded and controlled multinational trials is attributed to faster onset of action and greater antiplatelet effect. Moreover, neither agent is burdened by the variability of effect and resistance that has been an obstacle to optimal antiplatelet effects with clopidogrel. Although the greater antithrombotic effect of prasugrel is accompanied with a greater risk of bleeding, ticagrelor, which has reversible activity, has not been associated with an increase in major bleeding relative to clopidogrel. In addition, the reduction in all-cause mortality has provided greater benefit from employing ticagrelor in ACS patients. The data predict an important evolution in first-line antiplatelet therapy.