Tag Archives: prasugrel

Prevent Atherothrombotic Events? It’s Complicated

When researchers reported earlier this week at the American College of Cardiology’s annual meeting results from the TRA 2P-TIMI 50 trial, which tested a novel anticoagulant drug, vorapaxar, for preventing cardiovascular death, myocardial infarction (MI), and stroke in stable patients with cardiovascular disease, the results showed a questionable balance between benefit and bleeding risk that only looked good if you squinted and confined the analysis to patients with just a history of MI, no history of stroke, a body weight of at least 60 kg, and, ideally, those who were younger than 75 years old. Even within this pared-down universe, experts differed on whether vorapaxar had an unequivocal net benefit after taking into account the bleeding risk it caused.

But if vorapaxar someday gets FDA approval and appears on the U.S. market, physicians will face the tricky calculus of how to use it compared with the other new, potent antithrombotic drugs.

blood clot/courtesy Janice Carr; Public Health Image Library

Looking at vorapaxar’s performance in patients with stable cardiovascular disease, it was hard not to recall last November’s report on the ATLAS ACS 2-TIMI 51 trial, which tested adding a 2.5 mg b.i.d. dosage of another new anticoagulant drug, rivaroxaban, in acute coronary syndrome (ACS) patients also treated with aspirin and clopidogrel. In ATLAS, adding this small dose of rivaroxaban led to benefit and a bleeding risk that was strikingly similar to the pattern seen with vorapaxar in TRA 2P.  Rivaroxaban on top of aspirin and clopidogrel produced an absolute, 1.6% cut in the combined rate of cardiovascular death, MI, or stroke while boosting the rate of major bleeds by an absolute 1.2%, and the rate of intracranial bleeds by 0.2%. The new vorapaxar results showed that in the best-case subgroup, adding the drug to aspirin and clopidogrel cut cardiovascular death, MI, or stroke by an absolute 1.9%, while boosting major bleeds by 1.0% and intracranial hemorrhage by 0.2%.

A big difference in the two analyses was that the benefits and risk seen with 2.5 mg rivaroxaban was in the entire study population of 5,100 patients, with no need to resort to subgroup analyses. The vorapaxar result was in about 9,500 patients, roughly 70% of all patients enrolled in the trial. Another big difference was the major impact of rivaroxaban was on cutting cardiovascular deaths. Vorapaxar’s main effect was to lower nonfatal MIs. It cut cardiovascular deaths too, but not as well as low-dose rivaroxaban.

Many experts whom I spoke with at the meeting seemed confident that low-dose rivaroxaban is on track for FDA approval later this year for treating ACS patients. Whether Merck, the company developing vorapaxar, will seek FDA approval for its drug in stable patients based on the TRA 2P data remains to be seen.

But while rivaroxaban won’t receive labeling for treating non-ACS patients, all that separates an ACS patient and a patient who is stable but with a history of prior MI is time; in fact, just a few weeks or months. The point at which an acute ACS patient becomes a stable, post-MI patient is pretty murky. Would anyone consider treating a stable, post-ACS patient with low-dose rivaroxaban? The labeling probably won’t cover it, but will the temptation be there? And the what-ifs don’t stop there.

Both the low-dose rivaroxaban study and the vorapaxar study used aspirin and clopidogrel as standard, background treatment. But U.S. physicians are increasingly switching from clopidogrel to the newer, more potent antiplatelet drugs already on the market, prasugrel and ticagrelor, several experts told me at ACC. Putting a patient on prasugrel or ticagrelor plus aspirin will likely preclude any thought of also adding rivaroxaban, not to mention vorapaxar. These combinations have not been tested, and given the bleeding risks that these drugs pose individually, the idea of using them in combination is downright scary.

After several years when clopidogrel plus aspirin reigned alone as the top treatment for preventing atherothrombotic events, the last few years brought a flurry of new agents. How these drugs compare and relate to each other, and how they are optimally used alone or in combination, will take several more years to sort out.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Making Genotype a Routine Part of Drug Prescribing

Perhaps the boldest move to date to apply genotype information to drug prescribing, and to do it in a timely way to optimize the treatment a patient receives, launched in September at Vanderbilt University Medical Center in Nashville.

Vanderbilt physicians began routinely asking patients scheduled for coronary catheterization if they’d agree to have a small cell specimen genotyped using a commercially available chip that screens for 184 genetic polymorphisms that help determine the way a person metabolizes various prescription drugs. They decided to start with patients undergoing coronary cath, because many of these patients wind up getting a coronary stent and then require prolonged treatment with antiplatelet drugs, usually including clopidogrel. Some patients have a polymorphism in the gene for a protein involved in clopidogrel activation that impairs efficacy. Those patients either get a boosted clopidogrel dose or the pricier alternative, prasugrel. By mid November, 300 patients had undergone genotyping, with 10 poor metabolizers identified who received an alternate regimen.

image courtesy of Flickr user JaypeeOnline

Next up for expanding the program are patients scheduled for hip or knee replacement, because after surgery they’ll all go on an anti-coagulant drug, traditionally warfarin. Genotyping can help guide warfarin dosing during the first few days of treatment. (Since October, though, many patients began receiving dabigatran instead, an anti-coagulant that sidesteps the genotyping issue.)  Future patients to add to the genotyping list include those who are on or may soon start tamoxifen, azathioprine, 6-mercaptopurine, abacavir, codeine, or “virtually every antidepressant and most antipsychotics,” said Dr. Dan M. Roden, assistant vice-chancellor for personalized medicine at Vanderbilt and a driver and shaper of the program.

Although during rollout the program targets patients with a specific, imminent need for a certain drug, the broader concept is to have genetic information about variations in drug metabolism embedded in each patient’s medical record, so that it can automatically come into play whenever the patient gets prescribed a drug. “In the long perspective, it’s every 50-year-old,” because over the rest of ther lives they all stand a decent chance to receive some drug that carries a pharmacogenetic backstory, said Dr. Roden when I spoke with him last month in Chicago at the annual Scientific Sessions of the American Heart Association. Vanderbilt put “a huge amount of money into this,” he added, and it’s hoping to eventually persuade payers to foot the bill. So far Vanderbilt has supplied all the funding, because it believes this will improve outcomes and is also a great marketing tool.

A key element of Vanderbilt’s launch, which it says is the world’s first such program, was the careful wording of the alert that physicians get when their electronic pad identifies a patient with clopidogrel-activation deficiency. The pop-up’s text followed “a year of negotiations between lawyers, pharmacologists, pharmacists, and interventional cardiologists,” Dr. Roden said.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Filed under Cardiovascular Medicine, Drug And Device Safety, Family Medicine, Genomic medicine, Health Policy, Hospital and Critical Care Medicine, IMNG, Infectious Diseases, Internal Medicine, Medical Genetics, Oncology, Practice Trends, Primary care, Psychiatry, Surgery

Thinking Outside of Clopidogrel’s Black Box

From the annual meeting of the American College of Cardiology in Atlanta 

image courtesy of Flickr user jmcraftworks

The black box warning that the FDA slapped onto its labeling for the antiplatelet drug clopidogrel (Plavix) on March 12 became the talk of the American College of Cardiology’s annual meeting when it started a couple of days later. It also abruptly changed medicine’s antiplatelet playing field. 

Cardiologists, as well as primary care physicians, prescribe clopidogrel, often with aspirin, to many patients with coronary disease to help keep blood clots from forming inside their arteries. 

The FDA said it decided to impose the boxed warning because anywhere from 2%-14% of people are “poor metabolizers” of clopidogrel, which makes them unable to effectively convert it into its active form. In other words, when a poor metabolizer receives clopidogrel it’s as if the drug were never administered, because the person cannot change the drug to make it active. 

The implications of the FDA’s action were clear to many physicians at the ACC meeting. They now had three options for dealing with patients who needed antiplatelet therapy. They could: 

1. Treat patients with clopidogrel and then test their platelets’ reactivity to see if it had been properly blunted by clopidogrel treatment. If not, switch to a different drug. 

2. Test each patient before starting clopidogrel to see if they carried a mutation in one or both of their genes for the liver enzyme (cytochrome P2C19) responsible for producing the active metabolite of clopidogrel. If they carried a mutation, switch to a different drug. 

3. Skip either test and jump straight to an alternative drug. The most obvious alternative right now is prasugrel (Effient), an agent that’s very similar to cloipidogrel except it does not require enzymatic activation. 

What the FDA’s action precluded was maintaining the status quo. By adding the black box warning to clopidogrel last week, the FDA eliminated prescribing clopidogrel blindly as standard of care. 

—Mitchel Zoler (on Twitter @mitchelzoler) 

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Filed under Cardiovascular Medicine, Drug And Device Safety, Health Policy, IMNG, Internal Medicine, Medical Genetics, Practice Trends