Why prasugrel over clopidogrel

In addition, subjects who are poor responders to clopidogrel respond adequately to prasugrel. A mg dose of clopidogrel achieves maximal inhibition 2 to 4 hours after administration. Maintenance doses of 5, 10, and 15 mg prasugrel also achieve consistent and significantly greater platelet inhibition than the standard mg clopidogrel maintenance dose. The antiplatelet effects of the active metabolites of prasugrel and clopidogrel are about equally potent in vitro.

Prasugrel has been tested for efficacy in multiple studies. Three major clinical trials led to the approval of its use clinically.

After diagnostic angiography, patients were randomized to either clopidogrel mg loading dose [LD] followed by 75 mg daily or to 1 of 3 doses of prasugrel, a low-dose regimen 40 mg LD plus 7. Patients were treated with the study drug maintenance dose for 1 month with the co-administration of aspirin mg daily.

The study found no significant difference in non-CABG bleeding between those receiving prasugrel and clopidogrel at 30 days prasugrel 1. However, more TIMI minor bleeding events were detected in the prasugrel high-dose regimen group 3.

The trial also showed a numerically lower incidence of major adverse cardiac events at 30 days in the prasugrel-treated patients, a difference that did not achieve statistical significance as a secondary efficacy end point. During the first phase, prasugrel 60 mg loading dose was compared to clopidogrel mg loading dose with a primary end point of platelet inhibition at 6 hours.

In the second phase, patients received 10 mg maintenance dose of prasugrel for 14 days vs mg clopidogrel after the initial loading dose. On day 15 the patients were crossed over to the alternate maintenance treatment for an additional 2 weeks. As for the results, the IPA at 6 hours was significantly higher in the prasugrel group The enhanced inhibitory effect of prasugrel was seen as early as 30 minutes after the loading dose. Patients treated with prasugrel also had more consistent levels of inhibition with significantly lower interpatient variability.

In addition, the IPA after a 2 week maintenance dose was significantly greater in the prasugrel Of importance, prasugrel was well tolerated and only 2 patients in this group none in the clopidogrel group had TIMI minor bleeding before the cross over. It also showed its ability to yield a rapid, high and consistent level of platelet inhibition.

However, the question remained: Does a more potent platelet inhibition translate into a reduction in the atherothrombotic events clinically? The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel TRITON -TIMI 38 was a phase 3, randomized, double-blind, parallel group, multinational, clinical study designed to address this question and to evaluate for the first time in a large-scale clinical study whether a thienopyridine that results in a higher IPA results in improved clinical outcomes and is safe to use compared to the standard use of clopidogrel.

The loading dose was given any time between randomization and 1 hour after leaving the catheterization lab. Of importance is that the coronary anatomy had to be known to be suitable for PCI prior to randomization in all cases. Study subjects were followed at hospital discharge, 30 days, 90 days and at 3-month intervals for a total of 6 to 15 months. Key exclusion criteria included increased risk of bleeding, anemia, thrombocytopenia, known intracranial abnormalities, or the use of thienopyridines in the last 5 days.

The primary efficacy end point for the study was a composite of the rate of cardiovascular death, nonfatal MI or non-fatal stroke during the follow-up period. This occurred in patients This translates to a number needed to treat NNT of forty-five.

A significant benefit from prasugrel was seen by the first prespecified end point at 3 days HR 0. Benefit was seen across the ACS spectrum. Additionally, the inclusion of these extra adjudicated events doubled the benefit of prasugrel over clopidogrel and are needed for maintain statistical significance. Significant reductions were seen in the prasugrel group compared with the clopidogrel group in the rates of MI 9.

The findings on stent thrombosis were statistically significant irrespective of stent type. In a follow up study to TRITON-TIMI 38, Murphy et al hypothesized that prasugrel would reduce not only first events but also recurrent primary endpoint events and total events as compared to clopidogrel.

Even though these patients continue to be followed during the trial, any additional events they have are generally not included in the primary endpoint efficacy analysis.

This is important since in a real world setting these events are important for both the patient and the treating physician. In this analysis it was noted that patients with multiple events were older, had more co-morbidities at study entry including hypertension and diabetes and tended to be more females than males. Of importance, patients randomized to prasugrel were slightly older, less likely to be diabetic and more likely to have had multivessel PCI.

Results of this analysis showed that among patients with an initial non-fatal event, second events were significantly reduced with prasugrel compared to clopidogrel Overall, there was a reduction of total primary efficacy events with prasugrel vs clopi-dogrel rate ratio 0. The reduction in second events with prasugrel was consistent in several key subgroups, including the elderly, gender, stent type, index event, and creatinine clearance.

There was also a larger risk reduction in subsequent events in diabetics treated with prasugrel. These findings suggest that continued therapy with a regimen that provides higher levels of IPA remains important, even after an ischemic event has occurred.

Indeed, intensive anti-platelet therapy seems to be of added benefit to those who have already had such an event. The greater efficacy of prasugrel and its higher level of IPA come with a price. The most notable safety issue linked to the thienopyridines is their tendency to cause bleeding. This included a higher rate of life-threatening bleeding episodes. Additionally, in patients undergoing CABG, there was a significantly higher rate of bleeding in the prasugrel group Thus, prasugrel should not be the drug of choice for patients in whom CABG surgery is anticipated or cannot be ruled out because the coronary anatomy is unknown.

Fatal TIMI major bleeding occurred in a significantly higher number of patients treated with prasugrel 0. Intracranial bleeding was similar in both groups and occurred at a rate of 0.

It is interesting to note that approximately one-third of all bleeding events were recorded in the first day and almost half of all bleeding events were reported in the initial 10 days.

Although bleeding can cause serious morbidity and mortality, the most critical consequences of bleeding death, MI, and stroke , were included in the primary efficacy endpoint, where prasugrel was superior to clopidogrel. In addition, in a prespecified analysis of net clinical benefit, which included rates of efficacy endpoints and bleeding endpoints, prasugrel was noted to be superior to clopidogrel These 3 subgroups had no clinical benefit from prasugrel mainly due to higher risk of bleeding with the drug.

Bleeding events in older patients were more often fatal or symptomatic intracranial hemorrhage. Despite these differences, both clopidogrel and the newer P2Y 12 inhibitors such as prasugrel remain an integral part of drug therapies in the management of ACS.

The table below further lists the similarities and differences between clopidogrel and prasugrel:. Inhibits platelet activation and aggregation through irreversible binding of its active metabolite to P2Y 12 ADP receptors on platelets. Two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative and one mediated by multiple cytochrome P enzymes, mostly 2C To reduce thrombotic cardiovascular events, including stent thrombosis in patients with ACS who are to be managed with percutaneous coronary intervention PCI.

Single mg loading dose followed by mg once every day with or without food No dose adjustment required in hepatic impairment Limited experience in patients with moderate to severe renal impairment. Do not initiate therapy with prasugrel in patients likely to undergo coronary artery bypass graft CABG surgery.

Mark : No. There are a couple of major problems. One is that the dose of clopidogrel is too low. We know that the loading dose of clopidogrel should be mg to get platelet inhibition within two hours and that prasugrel 60 mg is not equivalent to clopidogrel mg. Andrea : A second problem is that the coronary anatomy had to be known to be amenable to PCI before patients were included in the study.

This is selection bias. Because we don't know the coronary anatomy ahead of time in many patients with acute coronary syndrome, it is likely that if the drug was started in all persons going to the cath lab some of whom would turn out not to have optimal coronary anatomy and would not benefit from PCI , the overall benefit would be less and there would be at least the same amount of bleeding.

Bob : Taking these two limitations into account, what about the results? The authors report a benefit in cardiovascular outcomes at However, for each cardiovascular death prevented by the use of prasugrel, its use resulted in approximately one additional episode of fatal bleeding.

Further, prasugrel needs to be avoided in patients with a history of stroke or transient ischemic attack. In these patients, prasugrel produced a significant increase in intracranial bleeding 2. Mark : It gets worse. It turns out that there is no benefit over clopidogrel in persons with a creatinine clearance less than 60 mL per minute, persons older than 65 years, and women.

This is a major part of the cohort that needs PCI! If we don't use prasugrel in these groups, the applicability of this drug is going to be very limited. Andrea : If the authors had used a mg clopidogrel loading dose, one could speculate whether the bleeding would likely have been higher in the clopidogrel group as well. Bob : The final annoying aspect of this paper is its misleading title.

It claims to compare prasugrel with clopidogrel in patients with acute coronary syndrome. This has nothing to do with patients with acute coronary syndrome whom we are planning to treat. It would have been more accurate to mention that these are patients who had acute coronary syndrome and were scheduled for PCI and in whom the coronary anatomy was known before the drug was started. Mark : For now, continue to use at least mg of aspirin as a loading dose for most patients with acute coronary syndrome.

Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Effects of clopidogrel vs. Boris Schnorbus , Boris Schnorbus. Oxford Academic. Andreas Daiber. Kerstin Jurk. Silke Warnke. Jochem Koenig. Karl J Lackner. Tommaso Gori.

Corresponding author. Biometrician of the study. Revision received:. Select Format Select format. Permissions Icon Permissions. Abstract Aims. Open in new tab Download slide. Endothelium , Thrombosis , Acute coronary syndromes , Stent.

Figure 1. Study protocol before and after amendment. Table 1 Patient characteristics. Treatment group. P -value. Age 31 Open in new tab. Figure 2. Table 2 Endothelial function data—FMD. Measurement time.

Comparisons averaged over time. Within-visit comparisons. Overall effect. Model-based contrast estimates averaged over time. Figure 3. Table 4 Platelet aggregation reactivity in hirudin-anticoagulated whole blood assessed by Multiplate-ADPtest.

Pairwise comparisons. Take home figure. Google Scholar Crossref. Search ADS. Google Scholar PubMed. Published on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals. Issue Section:. Download all slides. Supplementary data. View Metrics. Email alerts Article activity alert.

Advance article alerts. New issue alert. Receive exclusive offers and updates from Oxford Academic. See also Companion Article Mechanistic insights into the superior clinical efficacy of prasugrel over ticagrelor. Questions and answers on antithrombotic therapy: a companion document of the ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Questions and answers on antithrombotic therapy and revascularization strategies in non-ST-elevation acute coronary syndrome NSTE-ACS : a companion document of the ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.

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