Results from the 8,430 STEMI patients enrolled in the PLATO trial (presented last summer at the ESC and published simultaneously in the Lancet) are consistent with the main 18,000 patient trial and show that ticagrelor reduced the primary endpoint of MI, stroke or vascular death without causing an increase in major bleeding complications when compared to clopidogrel. The trial was presented by Philippe Gabriel Steg at the AHA.
“The results are very clear and actually very consistent with the overall trial results of the larger PLATO trial,” said Steg, in an AHA press release. The primary endpoint of MI, stroke or vascular death was reduced from 11% in the clopidogrel group to 9.3% in the ticagrelor group. Overall mortality was reduced from 6% to 4.9%. Definite stent thrombosis was reduced from 2.6% in the clopidogrel group to 1.6% in the ticagrelor group. Major bleeding occurred in 9.3% of clopidogrel patients versus 9.0% of ticagrelor patients.
Steg also said that “the benefit accrues over time so that the longer you treat, the greater the differences in event rates.” However, dyspnea occurred more frequently in the ticagrelor group than in the clopidogrel group (12.9% vs 8.3%).
Commenting on the mortality finding at an AHA press conference, Steg said it may be very significant since “we don’t often find new drugs in cardiovascular medicine that can save lives.”
Steg concluded by saying that “ticagrelor may become a new standard of care for the management of patients with STEMI intended for primary PCI.”
Steg also responded to a question about AstraZeneca’s recent disclosure that patients in North America did not derive the same benefit from ticagrelor as patients outside North America. Steg noted that only 1800 patients in North America, and that a plausible explanation for the difference, if real, is that North American patients tend to take higher doses of aspirin.
Click here for previous coverage of ticagrelor on CardioBrief.
Here is the press release from the AHA:
New reversible oral drug reduces cardiac events in primary PCI patients
ORLANDO, Fla., Nov. 15, 2009 — Acutely ill heart attack patients who received both aspirin and a new reversible oral anti-platelet medication had fewer cardiac events than patients on aspirin and the most commonly used, irreversible anti-platelet drug, researchers reported in a late-breaking clinical trial presentation at the American Heart Association’s Scientific Sessions 2009.
In the PLATelet Inhibition and Patient Outcomes (PLATO) trial, a subset of 8,430 patients who were in the midst of ST-elevation heart attacks (STEMI) and were scheduled for primary percutaneous coronary intervention (PCI) with stenting received the investigational drug ticagrelor or clopidogrel in addition to aspirin. Participants for the randomized, double-blind trial were recruited from 862 sites in 43 countries between 2006 and 2008.
The ticagrelor group suffered fewer cardiovascular events from the onset of the trial, and the benefits continued the longer patients took the drug during the year-long follow-up, said Philippe Gabriel Steg, M.D., lead investigator of the study. “The results are very clear and actually very consistent with the overall trial results of the larger PLATO trial, namely that there’s a reduction in the primary endpoint — a composite of incidence of heart attack, stroke or vascular death — with no increase in major bleeding complications compared to clopidogrel,” said Steg, professor of cardiology and director of the coronary care unit at Hôpital Bichat-Claude Bernard in Paris, France.
Bleeding is usually a concern with new antiplatelet agents. Since ticagrelor is a more potent agent than one of the American Heart Association/American College of Cardiology guidelines recommended medications, clopidogrel, bleeding was a concern. “The good news is that there was no sign of increased major bleeding regardless of how we defined it,” he said.
Following up to one year, 9.3 percent of the ticagrelor group met the primary endpoint, compared to 11 percent of the clopidogrel group — a 15 percent relative risk reduction for the investigational group. The patients in Steg’s analysis had STEMI and were scheduled to receive primary PCI — also known as angioplasty — and stenting during the acute phase of their heart attacks. The 4,201 patients randomized to the test group received 180 milligrams (mg) of ticagrelor during PCI, followed by 90 mg twice daily for six to 12 months. The other 4,229 patients received 300 mg of clopidogrel with a provision for an additional 300 mg during PCI, followed by 75 mg daily for six to 12 months. All patients in the trial also received daily aspirin therapy.
“STEMI is really the most acute form of coronary disease and represents roughly 40 percent of the patient group enrolled in the larger PLATO trial,” Steg said. “It is a common condition, and it is a high-risk condition for which the standard of care, clopidogrel, has clear drawbacks.”
“Clopidogrel’s drawbacks include a slower onset of effectiveness, which is not suited to the need for rapid effect in STEMI, and a modest and inconsistent anti-platelet effect — many patients respond well, but a sizeable unresponsive group remains at high risk of blood clots despite therapy,” Steg said. Clopidogrel also binds permanently to the platelets’ P2Y12 receptors, so its effect lasts seven to 10 days after the medication is stopped. In contrast, ticagrelor’s effect is direct and reversible, he said. “With ticagrelor, there is an actual disassociation between the drug and the P2Y12 receptor so that the drug does not bind permanently to the receptor, and the receptor and the platelet can regain function, with normal platelet clotting ability returning in about four days, which may explain the absence of increased bleeding with ticagrelor” Steg said. “However, ticagrelor does have off-target effects, which probably explain a side effect more commonly seen with ticagrelor than clopidogrel: dyspnea, or breathlessness, which affected 12.9 percent of ticagrelor patients and 8.3 percent of the clopidogrel group.”
Overall mortality was reduced with ticagrelor — from 6.0 percent to 4.9 percent, a relative reduction of risk of 18 percent. Likewise, the risk of new myocardial infarction and the risk of stent thrombosis were also reduced. “Furthermore, the benefit is not solely achieved during the acute phase, the first 30 days after angioplasty, but the benefit accrues over time so that the longer you treat, the greater the difference in event rates,” Steg said. “There is a strong rationale to prefer this new agent both in the acute (first 30 days) and in the late phase after a heart attack.”
Study funded by: AstraZeneca (manufacturer of the investigational drug).
Co-authors are: Richard C. Becker, M.D.; Christopher P. Cannon, M.D.; Hakan Emanuelsson, M.D., Ph.D.; Robert A. Harrington, M.D.; Jay Horrow, M.D.; Steen Husted, M.D., D.Sc.; Hugo Katus, M.D.; Robert F. Storey, M.D., D.M.; Lars C. Wallentin, M.D., Ph.D.
Disclosures: Research grant: Sanofi-Aventis, Servier Speakers bureau: Boehringer-Ingelheim, BMS, GSK, Medtronic, Sanofi-Aventis, Servier, The Medicines Company. Consulting/advisory board: Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Endotis, GSK, Medtronic, MSD, Nycomed, Sanofi-Aventis, Servier, and The Medicines Company.
###
Here is the press release from Astra Zeneca:
Ticagrelor (BRILINTA™) Demonstrated Greater Efficacy Over Clopidogrel in the Most Urgent Clinical Setting: Patients with ST-Segment Elevation Myocardial Infarction and Planned Percutaneous Coronary Intervention (PCI)
Late breaking data from PLATO sub-analysis presented at the American Heart Association Scientific Sessions
November 15, 2009 – Orlando, FL /PRNewswire/ — AstraZeneca (NYSE: AZN) today announced results of a PLATO sub-analysis in the most serious type of Acute Coronary Syndrome (ACS) patients, those with ST Segment Elevation Myocardial Infarction (STEMI). In this setting, ST segment elevation indicates total obstruction of a coronary artery which warrants emergency surgery with angioplasty, a procedure termed primary Percutaneous Coronary Intervention or “PCI,” in order to restore flow, salvage the heart muscle (myocardium) from infarction and reduce mortality.
The sub-analysis showed that, compared to clopidogrel (Plavix®/Iscover®), treatment with ticagrelor (BRILINTA™) resulted in a reduction of cardiovascular events (composite of CV death, heart attack and stroke) for up to a year (ticagrelor vs. clopidogrel, 9.3% vs. 11.0%, P=0.02), without an increase in major bleeding (9.0% vs. 9.3%, P=0.63).1 These efficacy findings were driven by a statistically significant reduction in heart attacks (myocardial infarction) (4.7% vs. 6.1%, P=0.01). For these STEMI patients, the benefit observed with ticagrelor increased over time.1
Ticagrelor also demonstrated effects across several secondary efficacy endpoints including MI, stent thrombosis, and the composite of MI, stroke and all-cause mortality.1 There was an 18% relative reduction in all cause mortality at one year from 6.0 to 4.9% (P=0.04) with ticagrelor over clopidogrel.
The pre-specified sub-analysis of the ACS STEMI patients looked at approximately 45% (8,430 patients) of the overall PLATO study population. These data were presented today during the late-breaker session at the annual American Heart Association (AHA) Scientific Sessions in Orlando, FL. 1
“Patients with STEMI need to undergo emergency PCI. They are particularly at risk of serious complications, so also require rapidly active antithrombotic agents,” commented Professor Gabriel Steg, Cardiologist at Hopital Bichat, Assistance Publique – Hopitaux de Paris (AP-HP), Professor of Cardiology at the University Paris 7, Paris, France and Principal Investigator of the PLATO STEMI sub-analysis. “In PLATO, we studied a broad patient population to investigate ticagrelor’s efficacy in patients that are typical of those we see in clinical practice. As previously shown in patients undergoing invasive procedures, and now in STEMI patients, these results are consistent with the reduction of CV events without an increase in major bleeding, seen in the overall PLATO trial.”
About ACS STEMI
There are three types of ACS events: ST Segment Elevation Myocardial Infarction (STEMI) usually reflecting complete blockage of coronary artery, non-ST Segment Myocardial Infarction (N-STEMI), usually reflecting partial blockage of coronary artery, and unstable angina.2A,2B Patients with STEMI represent a high-risk subgroup of ACS patients and a large number of these patients will undergo rapid PCI treatment and are particularly at risk of serious, and potentially deadly, complications.1,2A,3A,3B
About PLATO STEMI sub-analysis
In the PLATO study, 4,201 STEMI patients were allocated to ticagrelor 180 mg loading dose followed by 90 mg twice daily plus aspirin, and 4,229 to clopidogrel 300 mg loading dose (with provision for 300 mg clopidogrel at PCI) followed by 75 mg daily for 6-12 months, plus aspirin.1
About Coronary Artery Disease (CAD)
Coronary artery disease, also called coronary heart disease, is most often caused by atherosclerosis, and can lead to acute coronary syndrome (ACS).3C
About Ticagrelor
Ticagrelor (BRILINTA™) is an investigational oral antiplatelet treatment for ACS. Ticagrelor is a reversibly binding oral adenosine diphosphate (ADP) receptor antagonist. It selectively inhibits P2Y12, a key target receptor for ADP. ADP receptor blockade inhibits the action of platelets in the blood, reducing recurrent thrombotic events.3D,3E,4A,4B
BRILINTA is the first in a new chemical class, the CPTPs (cyclo-pentyl-triazolo-pyrimidines) and is chemically distinct from the thienopyridines, such as clopidogrel and prasugrel.4C,5A
AstraZeneca has proposed the name BRILINTA™ in the US. If approved by the FDA, it will serve as the trade name for ticagrelor. BRILINTA is a trademark of the AstraZeneca group of companies.
About AstraZeneca
AstraZeneca is engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and in the supply of healthcare services. AstraZeneca is one of the world’s leading pharmaceutical companies with global healthcare sales of $31.6 billion and is a leader in gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infectious disease medicines. In the United States, AstraZeneca is a $13.5 billion dollar healthcare business.
For more information about AstraZeneca in the US or our AZ&Me™ Prescription Savings programs, please visit: www.astrazeneca-us.com.
References:
1Steg G et al, Comparison of Ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: results from the PLATelet inhibition and patient Outcomes (PLATO) trial. Presentation at AHA 2009. Final Program Number LBCT.01
2About.com: Heart Disease
a. STEMI – ST Segment Elevation Myocardial Infarction, Richard N. Fogoros, M.D., Paragraph 2, Lines 1 – 5
b. NSTEMI – Non ST Segment Myocardial Infarction, Richard N. Fogoros, M.D., Paragraph 2, Lines 1 – 3
3American Heart Association.
a. http://www.americanheart.org/presenter.jhtml?identifier=3061532. Glossary. ST-elevation myocardial infarction (STEMI). Lines 1 – 3.
b. http://www.americanheart.org/presenter.jhtml?identifier=4454 Percutaneous Coronary Interventions: ACC/AHA/SCAI Guidelines. Paragraph 2
c. http://www.americanheart.org/presenter.jhtml?identifier=3010002. About Acute Coronary Syndrome. Page 1, Paragraph 1, Lines 1-4.
d. http://www.americanheart.org/presenter.jhtml?identifier=4438. Antiplatelet Agents, Paragraph 1, Lines 1-3
e. http://www.americanheart.org/presenter.jhtml?identifier=4438 Blood Clots Form, Paragraph 1, Lines 1-4
4James, S. et. al. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rational, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. American Heart Journal. 2009:157(4): 599-605.
a. Background. Page 600. Column 2, Paragraph 1, Lines 1 – 3
b. Background. Page 600. Paragraph 1, Lines 1-4
c. Background. Page 600. Paragraph 2, Lines 1-4
European Heart Journal.
a. Husted, Steen. Eur Heart J. Supplements 2007;(Supplement D): D20-D27
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[...] Ticagrelor, der Clopidogrel-Konkurrent von AstraZeneca, hat auch in einer großen Subanalyse der PLATO-Studie seine Überlegenheit belegt. Die Daten der Subanalyse sind gerade auf dem Kardiologen-Kongress der „American Heart Association“ in Orlando von präsentiert worden. Untersucht wurde die Wirksamkeit der beiden Antithrombotika bei Patienten mit ST-Hebungsinfarkt (STEMI). Ergebnisse laut Dr. Philippe Gabriel Steg, der die Studie in Orlando vorgestellt hat:: Ticagrelor reduzierte auch bei den 8430 Patienten mit STEMI signifikant besser als Clopidogrel den primären kombinierten Endpunkt aus Herzinfarkt, Schlaganfall oder kardiovaskulärer Tod, ohne dass mehr schwere Blutungen auftraten. In der Ticagrelor-Gruppe (4201 Patienten) kam es während der Verlaufsdauer von einem Jahr bei 9,3 % der Patienten zum primären Endpunkt, in der Clopidogrel-Gruppe (4229 Patienten) dagegen bei 11 %. Auch bei der Gesamtmortalitätsrate schnitt das AstraZeneca-Präparat mit 4,9 % versus 6 % signifikant besser ab. Deutlich war mit 2,6 % im Vergleich zu 1,6 % auch der Unterschied bei den Stent-Thrombosen. Die Blutungsraten betrugen 9,3 % (Clopidogrel) und 9,0% (Ticagrelor). Allerdings klagten in der Ticagrelor-Gruppe signifikant mehr Patienten über Dyspnoe (12,9 % versus 8,3 %). Auffallend war allerdings, dass die US-Patienten (1800) der internationalen, von AstraZeneca finanzierten Multizenter-Studie nicht ebenso so deutlich von dem neuen Antithrombotikum profitierten. Als eine mögliche Erklärung nannte Steg den bei US-Patienten häufig höheren ASS-Verbrauch. Die jetzt präsentierten Daten seien eindeutig und stimmten mit denen der Gesamt-Studie PLATO bei 18 000 Patienten überein, sagte Steg. Zur Erinnerung: In der Hauptstudie, die dieses Jahr auf dem Europäischen Kardiologen-Kongress vorgestellt wurde, betrug die Differenz beim primären Endpunkt 1,9 Prozentpunkte (9,8 versus 11,7 %). Link: Cardiobrief [...]
[...] Ticagrelor found beneficial in STEMI subset of PLATO [...]