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Developed in Canada and conducted by researchers from the University of Ottawa Heart Institute, in partnership with Spartan Bioscience, the world’s first bedside genetic test has received acknowledgment by The Lancet, the world’s leading general medical journal.

The article Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial, reports on the use of a simple cheek swab test, the Spartan RX CYP2C19, performed by nurses at the patient’s bedside. This revolutionary technology allows doctors to rapidly identify patients with a genetic variant known as CYP2C19*2. Cardiac stent patients with this variant are at risk of reacting poorly to standard anti-platelet therapy with Plavix® (clopidogrel).

The study demonstrated that tailored drug treatment therapy made possible by the genetic testing successfully protected all of the patients with the at-risk genetic variant from subsequent adverse events, while 30 per cent of patients treated with standard therapy did not receive adequate protection.

“For the first time in medicine, nurses were able to perform DNA testing at the patient’s bedside. This is a significant step towards the vision of personalized medicine,” said Dr. Derek So, Interventional Cardiologist at the University of Ottawa Heart Institute (UOHI), and principal investigator of the RAPID GENE study.

Study Details

The RAPID GENE study enrolled 200 patients who were being treated with cardiac stenting for an acute coronary syndrome or stable angina. Patients were randomized to a treatment strategy of rapid point-of-care genotyping and Effient® (prasugrel) for CYP2C19*2 carriers, or to standard therapy with Plavix® (clopidogrel). The Spartan RX CYP2C19 bedside DNA test was performed by nurses who received a 30-minute training session, but had no prior laboratory training. The test had a sensitivity of 100% and a specificity of 99.4% compared with DNA sequencing. For CYP2C19*2 carriers, treatment with prasugrel completely eliminated High on-treatment Platelet Reactivity (HPR). HPR is a marker for patients at risk of complications after stenting. In contrast, 30.4% of carriers receiving clopidogrel had HPR at 1 week.

BOSTON, MA—Percutaneous coronary intervention (PCI), also known as coronary angioplasty or angioplasty, is a procedure used to treat acute coronary syndromes. PCI involves opening a blocked blood vessel by threading and inflating a balloon-tipped tube into the vessel. Sometimes a stent is also inserted to keep the blood vessel open.

While undergoing PCI treatment, doctors usually give patients medicine to prevent complications that may occur from the procedure.

In a new study by researchers at Brigham and Women’s Hospital (BWH), types and timing of cardiovascular disease and heart attack (CVD/MI) complications were tracked in patients undergoing PCI after an acute coronary syndrome and taking medications to prevent these complications.

The study is being presented at the American College of Cardiology 2012 Annual Scientific Session, March 24 to 26 in Chicago.

Utilizing patients from the TRITON-TIMI 38 study, researchers examined 12,844 patients who had at least one stent and were randomized to receive either the anti-blood clotting drugs prasugrel (Effient) or clopidogrel (Plavix). These drugs work by blocking activation of platelets (a component in blood involved in clotting).

The researchers observed the patients over a median follow-up of 14.5 months.

Researchers classified CVD/MI events under three categories: stent thrombosis (when a blood clot forms in the stent), procedural-related (in the setting of PCI or bypass surgery), or spontaneous (not related to stents nor procedures, but indicating a thrombosis in a different artery than the one that caused the first acute coronary syndrome event).

There were 1,306 CVD/MI events. 186 (14 percent) were stent thrombosis-related, 606 (46 percent) were procedural-related, and 514 (40 percent) were spontaneous.

For events occurring after 30 days, the majority were spontaneous (383, 81.2 percent), followed by stent thrombosis-related (63, 13.5 percent), and procedural-related (22, 4.7 percent).

CVD/MI events that occurred within the first 30 days tended to be stent thrombosis-related and procedural-related. Spontaneous CVD/MI events occurred more often in the later phase (more than 30 days after PCI).

When comparing the two drugs in the study, prasugrel reduced the incidence of CVD/MI in each event category, both early and late, with the benefit most marked among stent thrombosis-related events.

The researchers concluded that more potent anti-blood clotting drugs directly reduces complications from PCI, as well as preventing the formation of new, symptomatic thrombotic lesions in other arteries.

“These data from TRITON-TIMI 38 provide clinicians with new information regarding the timing and benefit of more potent anti-platelet agents following PCI for an acute coronary syndrome,” said Benjamin Scirica, MD, MPH, BWH Cardiovascular Division, Department of Medicine, and lead study author. “It reminds us that these agents are not only preventing stent-related complications, which tend to occur early after PCI, but are also preventing the formation of new, spontaneous, thrombotic lesions throughout the coronary artery tree.”

SAN FRANCISCO, CA – NOVEMBER 9, 2011 – A clinical trial comparing prasugrel to clopidogrel for patients with high on-clopidogrel platelet reactivity (HCPR) following percutaneous coronary intervention (PCI) was ended early due to relatively few occurrences of cardiac death or myocardial infarction – the primary endpoint – at six month follow up.

Results of the TRIGGER-PCI (Testing platelet Reactivity In patients underGoing elective stent placement on clopidogrel to Guide alternative thErapy with pRasugrel) trial were presented today at the 23rd annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium, sponsored by the Cardiovascular Research Foundation.

The risk of ischemic events after percutaneous coronary intervention (PCI) is elevated in patients with high on-clopidogrel platelet reactivity (HCPR). Novel P2Y12-receptor antagonists, such as prasugrel, are more potent than clopidogrel and may, thus, improve outcome with respect to ischemic events, but may also increase bleeding risk.

The trial was a multi-center, double-blind, randomized controlled trial. Platelet reactivity was assessed two to seven hours after the first maintenance dose of clopidogrel 75 mg on the day after PCI following loading with clopidogrel 600 mg and randomized to either prasugrel or clopidogrel. TRIGGER-PCI aimed to randomize 2,150 patients to have a 93% power for detecting a 50% relative risk reduction on prasugrel in the primary study endpoint (cardiovascular death or myocardial infarction within six months).

The study was terminated prematurely for futility at March 18, 2011 at which 236 patients completed the six-month follow up. Only one clinical endpoint, a peri-procedural myocardial infarction, was observed.

“High on-clopidogrel platelet reactivity (>208 PRU by VerifyNow P2Y12 test) was observed less frequently than expected,” said Dietmar Trenk PhD. Dr. Trenk is Professor and Head of Clinical Pharmacology at Herz-Zentrum Bad Krozingen in Germany.

Dr. Trenk noted that the trial demonstrated that compared with standard-dose clopidogrel 75 mg, prasugrel 10 mg substantially decreased platelet reactivity in patients with high on-clopidogrel platelet reactivity after elective PCI.

“Given the low event rate in elective PCI patients without peri-procedural complications, it was not possible to assess the risk/benefit ratio with prasugrel treatment. Therefore, the study was terminated prematurely for futility,” Dr. Trenk said.

The trial is sponsored by Eli Lilly and Company and Daiichi Sankyo Co., Ltd. Dr. Trenk reported consulting fees/honoraria and speaker honoraria from both companies, AstraZeneca and Sanofi-Aventis.

Source: Eurekalert

Professor Storey has led UK investigations of ticagrelor and was a member of the international committee that conducted the PLATO study, a trial of over 18 thousand patients in over 40 countries around the world. The results of the PLATO study were first presented at the European Society of Cardiology congress in 2009, showing that ticagrelor was more effective for heart attack patients than clopidogrel in reducing death and recurrent heart attack.

A new analysis of the PLATO study presented this year at the American College of Cardiology showed that ticagrelor is just as effective at reducing deaths in patients over the age of 75 as in younger patients. Professor Storey commented: “Our new findings really highlight the universal applicability of the treatment.”

Ticagrelor was made available in the UK in December 2010 but has not yet been adopted across most of the UK due to cost concerns. Clopidogrel has a very low cost as it is available in generic forms, whereas ticagrelor is more expensive at around £55 per month. However, the excess drug cost of ticagrelor is offset to some extent by its greater effectiveness which reduces the need for heart operations.

Professor Storey commented: “Many people are dying avoidably in the year after having a heart attack due to delays introducing this new treatment. These new findings provide yet further evidence in support of making the drug available to patients in the UK. We’re pleased that the Scottish Medicine Consortium recently approved ticagrelor, on the basis that the initial expense of the drug is offset to a significant extent by the resultant savings, such as reduced need for procedures. In England, a verdict from NICE is awaited but final guidance is not expected until October.”

One of the problems with clopidogrel is that about a quarter of people in the UK have a genetic variant that reduces the effect of the drug and are at greater risk. A sub-study of the PLATO trial was published in the Lancet confirming that patients treated with clopidogrel, who have such a genetic variant, have a slightly higher risk in the first month following heart attack but ticagrelor is not affected by this variant and is still more effective than clopidogrel, regardless of a patient’s genetic make-up.

A common side-effect of ticagrelor is a sense of breathlessness which is usually mild and well-tolerated. Professor Storey presented data at the European Society of Cardiology meeting in 2010 showing that even patients who develop this side-effect still seem to have the reduced mortality risk compared to clopidogrel-treated patients. Another analysis led by Professor Storey showed that patients who develop breathlessness on ticagrelor do not show any problems on heart or lung tests, providing reassurance about the benign nature of ticagrelor-related breathlessness.

Professor Storey has been involved with the development of ticagrelor and related drugs for the past 15 years. 90 patients from Sheffield, with acute coronary syndrome, were recruited for the PLATO trial, which involved over 18,000 cardiac patients worldwide. One of the questions that is currently unanswered is whether continuing ticagrelor beyond 1 year after a heart attack will lead to continued benefit. This question will be addressed by the PEGASUS study which has recently started in the UK and many other countries, recruiting patients who are within 2 years of completing their one year course of treatment following a heart attack.

Professor Storey commented: “PEGASUS is an exciting study that will recruit 21,000 patients around the world, looking at whether ticagrelor added to aspirin is more effective at preventing problems related to clotting in the arteries than the standard anti-clotting treatment of aspirin only. Another study (ATLANTIC) planned to start in the next few months will also assess whether it is more effective to treat patients with full-blown heart attack with ticagrelor in the ambulance rather than wait until patients arrive at the hospital to have the blocked artery opened by balloon angioplasty.”

CHICAGO – Modifying a patient’s dosage of the antiplatelet drug clopidogrel for 6 months depending on the patient’s level of platelet reactivity did not result in combined lower rates of nonfatal heart attack, stent thrombosis (clot) and cardiovascular death in patients who had a procedure such as balloon angioplasty and received a drug-releasing coronary stent, according to a study in the March 16 issue of JAMA.

Current guidelines recommend treating patients undergoing percutaneous coronary intervention (PCI; procedure such as balloon angioplasty used to open narrowed coronary arteries) and drug-eluting stent implantation with a combination of aspirin and P2Y12 (compound found on the surface of blood platelet cells and an important regulator in blood clotting) antagonist for at least 1 year. But several studies have suggested that patients with high platelet reactivity during treatment with clopidogrel are at an increased risk of cardiovascular events after PCI. A treatment strategy for this issue has not been well defined, according to background information in the article.

Matthew J. Price, M.D., of Scripps Translational Science Institute, La Jolla, Calif., and colleagues conducted the Gauging Responsiveness with A VerifyNow assay—Impact on Thrombosis And Safety (GRAVITAS) trial to determine whether high-dose clopidogrel is superior to standard-dose therapy for the prevention of cardiovascular events after PCI in patients with high on-treatment reactivity. The randomized trial included 2,214 patients with high on-treatment reactivity (measured 12 to 24 hours after PCI) with drug-eluting stents at 83 centers in North America between July 2008 and April 2010. Patients received high-dose clopidogrel (600-mg initial dose, 150 mg daily thereafter) or standard-dose clopidogrel (75 mg daily) for 6 months. The primary outcome measured was the 6-month incidence of death from cardiovascular causes, nonfatal heart attack, or stent thrombosis. Safety measurements included severe or moderate bleeding.

The researchers found that the rate of death from cardiovascular causes, nonfatal heart attack, or stent thrombosis was not different with high-dose compared with standard-dose clopidogrel in the patients with high on-treatment reactivity (25 (2.3 percent) vs. 25 [2.3 percent]). In an analysis, the event rates in the 2 groups after 30 days were (20 [1.9 percent] vs. 17 [1.6 percent]), respectively.

The reduction in on-treatment reactivity at 30 days and at 6 months after randomization was significantly greater with high-dose than with standard-dose clopidogrel. High-dose clopidogrel was associated with an absolute 22 percent lower rate of high on-treatment reactivity compared with standard-dose clopidogrel at 30 days and 6 months (40 percent vs. 62 percent; and 36 percent vs. 60 percent, respectively).

Severe or moderate bleeding was not increased with the high-dose regimen.

“In conclusion, high-dose clopidogrel for 6 months in patients with high on-treatment platelet reactivity 12 to 24 hours after PCI with drug-eluting stents did not reduce the rate of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis compared with standard-dose clopidogrel. The results of GRAVITAS do not support a uniform treatment strategy of high-dose clopidogrel in patients with high on-treatment reactivity identified by a single platelet function test after PCI. Alternative treatment strategies incorporating platelet function testing merit further investigation,” the authors write.

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: An Initial Experiment With Personalized Antiplatelet Therapy

Paul A. Gurbel, M.D., and Udaya S. Tantry, Ph.D., of the Sinai Hospital of Baltimore, comment on the findings of this study in an accompanying editorial.

“… the GRAVITAS investigators have conducted the largest trial of personalized antiplatelet therapy thus far. The valuable information gained from the GRAVITAS trial can inform future trials. Even though GRAVITAS demonstrated that platelet function testing after drug-eluting stent placement does not improve outcomes if high-dose clopidogrel is used as the remedy, it is hoped that future studies evaluating different platelet function cutpoints and more potent P2Y12 inhibitors will be effective.”