FDA Advisory Panel Recommends Against Approval Of Cangrelor Reply

The FDA’s Cardiovascular and Renal Drugs Advisory Committee today recommended against the approval of cangrelor, the investigational new antiplatelet drug from the Medicines Company. In a 7-2 vote the panel first rejected an indication  for the reduction of thrombotic cardiovascular events including stent thrombosis in patients undergoing PCI.

The panel also voted unanimously to reject a second indication…

Click here to read the full post on Forbes.

 

 

About these ads

Some Patients With Minor Stroke Or TIA May Benefit From Early Clopidogrel And Aspirin Reply

Some people with minor ischemic stroke or transit ischemic attack (TIA) may benefit from dual antiplatelet therapy with aspirin and clopidogrel, according to a large new study from China published in the New England Journal of Medicine. In the immediate period following a TIA or minor stroke people are at high risk for having a major stroke. Aspirin is known to cause a modest reduction in recurrent events. More potent antiplatelet agents like clopidogrel may also be beneficial, but have not been well studied in the early phase and may increase the risk of bleeding complications, including the conversion of an ischemic stroke into a worse hemorrhagic stroke.

Investigators in the CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) trial randomized 5,170 patients within 24 hours of a minor ischemic stroke or high-risk TIA to three months of treatment with either clopidogrel and aspirin or placebo and aspirin. At 90 days the rate of stroke was 8.2% in the combination group versus 11.7% in the aspirin-alone group (hazard ratio 0.68, CI 0.57-0.81, p<0.001). There were also significant reductions…

Click here to read the full story on Forbes.

 

Cangrelor During PCI May Reduce Ischemic Events Reply

In the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) trial, the intravenous platelet inhibitor cangrelor was tested for its effect on ischemic events associated with PCI. Cangrelor is a potent, fast-acting and reversible  agent. Results of the trial were presented at the ACC in San Francisco and published simultaneously in the New England Journal of Medicine.

A total of 11,145 PCI patients were randomized to a bolus and infusion of cangrelor or to a loading dose of clopidogrel. A primary endpoint event — death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours — occurred in 4.7% of the cangrelor group versus 5.9% of the clopidogrel group (adjusted OR, 0.78; 95% CI, 0.66-0.93; P=0.005). The authors calculated that 84 patients would need to be treated with cangrelor instead of clopidogrel to prevent one primary endpoint event.

Note to readers: Don’t miss this fascinating post on CardioExchange in which CHAMPION PHOENIX co-chair Deepak Bhatt responds to questions raised by Rick Lange and David Hillis in their New England Journal of Medicine editorial.

Click here to read the full story on Forbes.

Early Results: Antiplatelet Drug Cangrelor Appears Effective For PCI Reply

The experimental antiplatelet drug cangrelor was superior to traditional clopidogrel in reducing ischemic events at 48 hours in PCI patients, according to the Medicines Company, which is developing the drug. The company today announced positive results from the phase 3 CHAMPION PHOENIX trial, a randomized, double-blind study comparing intravenous cangrelor to oral clopidogrel in PCI patients. The primary endpoint was the composite of death, MI, revascularization and stent thrombosis at 48 hours.

Click here to read the full story on Forbes.

 

Danish Survey Finds Clopidogrel Less Effective In Diabetics Reply

A large nationwide survey of MI survivors in Denmark provides new information about the efficacy of antiplatelet therapy with clopdiogrel in patients with diabetes. In a paper published in JAMACharlotte Andersson reports on 58,851 MI patients, 12% of whom had diabetes and 60% of whom received clopidogrel.

As expected, diabetics had a worse outcome than nondiabetics: the composite endpoint of recurrent MI and all-cause mortality occurred in 25% of diabetics compared with 15% of the nondiabetics. Overall mortality was 17% in the diabetic group compared with 10% in the nondiabetic group.

Clopidogrel was less effective in diabetics than in nondiabetics in reducing all-cause mortality and CV mortality:

  • All-cause mortality risk reduction: 11%for diabetics versus 25% for nondiabetics (p value for interaction = .001)
  • CV mortality risk reduction: 7% (nonsignificant) for diabetics versus 23% for nondiabetics (p value for interaction = .01)

The results lend support to the hypothesis that “there may be a difference of effect of clopidogrel among those with diabetes compared with those without it,” wrote the authors. After acknowledging that “use of clopidogrel may still translate into a significant reduction in event rates for patients with diabetes,” they then raise the “possibility that patients with diabetes may benefit from a more potent platelet inhibitor strategy to achieve a relative risk reduction similar to patients without diabetes.”

In an accompanying editorial, Deepak Bhatt lends support to their suggestion, writing that it is plausible to suspect that there is “something about patients with diabetes that makes them less likely to respond to standard antiplatelet therapy.” Compared with nondiabetics, diabetics with coronary artery disease have increased platelet reactivity.  Bhatt writes that the newer and more potent antiplatelet agents prasugrel and ticagrelor may be more effective in diabetics, though they may also cause an increase in the risk of bleeding, and they cost more than clopidogrel, which has now gone generic.
Click here to read the press release from JAMA…

TRILOGY At ESC: No Advantage For Prasugrel Over Clopidogrel In Medical ACS Patients Reply

The newer antiplatelet agent prasugrel was no better than the old standby clopidogrel for treating patients with acute coronary syndrome (ACS) who are not undergoing revascularization. The results of the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial were presented by Matt Roe at the European Society of Cardiology meeting in Munich and published simultaneously in the New England Journal of Medicine.

In the primary analysis of the trial, prasugrel (10 mg daily) was compared with clopidogrel (75 mg daily) in 7243 ACS patients younger than age 75. At 17 months, the rate of CV death, MI, or stroke did not differ significantly between the two groups:

  • 13.9% in the prasugrel group versus 16.0% in the clopidogrel group (hazard ratio [HR] for prasugrel, 0.91; 95% CI, 0.79-1.05, P=0.21)

The results were similar in a secondary analysis, which also included 2083 patients who were age 75 or older and who received either  low-dose prasugrel (5 mg daily) or the standard clopidogrel dose.

In a separate prespecified analysis, prausgrel patients under age 75 had a decreased risk for multiple recurrent ischemic events (HR, o.85; 95% CI, 0.72-1.00, P=0.04). According to the TRILOGY investigators, this finding is consistent with results from the earlier TRITON trial. TRITON compared prasugrel with clopidogrel in ACS patients undergoing revascularization; recurrent ischemic events in the prasugrel group were reduced by 30%, with most of the reduction occurring later in the trial. “Although this observation is exploratory,” the TRILOGY investigators wrote, ” it raises the question of whether investigation of the multiplicity of ischemic events is warranted in future secondary-prevention trials, rather than solely analyzing the time to the first event, as has been traditional” in previous studies.

The prasugrel and clopidogrel groups did not differ significantly in the rate of severe and intracranial bleeding. However, within the younger subgroup (taking the higher prasugrel dose), prasugrel recipients had more major and minor bleeding complications than clopidogrel recipients did — a reflection, the authors wrote, of “the more intense platelet inhibition with prasugrel.”

An exploratory analysis found that in the main group of patients under the age of 75, the Kaplan-Meier curves for the primary endpoint and for the individual components of the endpoint were not different for the first year but diverged afterward in favor of prasugrel. “The reasons for this finding remain uncertain,” the investigators wrote.

A subgroup analysis suggested the possibility that prasugrel might be more effective than clopidogrel in current or recent smokers, in patients who underwent angiography prior to randomization, and in patients taking a proton-pump inhibitor.

Sanjay Kaul provided the following comment:

“I find the TRILOGY investigators’ focus on time-dependent treatment effect (greater benefit after 12 months of treatment exposure) and recurrent events, both of which favor prasugrel, an attempt at cherry picking the data that portray prasugrel in the best light. The bottom line is that given the lack of a statistically discernible difference in the primary efficacy endpoint coupled with an increase in TIMI major or minor bleeding and increased cost associated with prasugrel, it is hard to make a case for prasugrel over clopidogrel treatment in low- to moderate-risk patients with unstable angina and NSTEMI who do not undergo revascularization. Although TRILOGY was not adequately powered to detect a cancer signal, the lack of increase in new nonbenign neoplasms is somewhat reassuring.”

Republished with permission from CardioExchange, a NEJM group publication.

Ticagrelor Joins Clopidogrel And Prasugrel In Updated NSTEMI Guidelines Reply

Ticagrelor (Brilinta, AstraZeneca) gains equal standing with prasugrel (Effient, Lilly) and clopdiogrel in the newly released focused update of the ACCF/AHA guidelines for unstable angina and non-ST-elevation myocardial infarction (NSTEMI). The change had been widely anticipated since last year’s FDA approval of ticagrelor.

“We have put it on equal footing with two other antiplatelet medications, clopidogrel and prasugrel,” said Hani Jneid, the, lead author of the update, in a press release issued by the AHA.

As part of the standard of dual-antiplatelet therapy (DAPT), aspirin should be given immediately to patients with unstable angina and NSTEMI. Aspirin use should be continued for “as long as it is tolerated.”

The document offers a highly detailed, near-Talmudic analysis of the literature, with a great deal of attention devoted to analysis of the  TRITON-TIMI 38 trial of prasugrel and the PLATO trial of ticagrelor. Overall, the committee concluded:

This guideline explicitly does not endorse one of the P2Y12 receptor inhibitors over the other.

However, based on data from the trials, the document provide ssome advice about the selection of the P2Y12 receptor inhibitors in specific situations, and related issues involving clopidogrel resistance.

–Because prasugrel was administered only after PCI had been planned, the writing group “does not recommend that prasugrel be administered routinely to patients with UA/NSTEMI before angiography.”

–The writing group cautions “clinicians about the potential increased bleeding risks associated with prasugrel and ticagrelor compared with clopidogrel in specific settings and especially among the subgroups identified in the package insert and clinical trials.”

–The document reviews at length the issue of clopidogrel resistance, but concludes “there is little information about the use of strategies to select patients who might do better with newer P2Y12 receptor inhibitors.”

–On genotype testing for loss-of-function CYP2c19 alleles: “On the basis of the current evidence, it is difficult to strongly recommend genotype testing routinely in patients with ACS, but it might be considered on a case-by-case basis, especially in patients who experience recurrent ACS events despite ongoing therapy with clopidogrel.”

–On platelet function testing: “any strong recommendation regarding more widespread use of such testing must await the results” of ongoing trials…. the prudent physician should maintain an open yet critical mind-set about the concept until data are available…”

–On the use of proton pump inhibitors and clopidogrel: “The expert consensus statement does not prohibit the use of PPI agents in appropriate clinical settings, yet highlights the potential risks and benefits from use of PPI agents in combination with clopidogrel.”

Click here to read the press release from the AHA…

FDA Approves Generic Clopidogrels As Plavix Loses Patent Protection 1

For the second time in the past six months, a cardiology mainstay drug has lost patent protection and gone generic. Today the FDA announced that it had approved several generic versions of clopidogrel (Plavix), the antiplatelet drug that for many years was the second best-selling drug in the world. Last November the best-selling drug of all time, Lipitor (atorvastatin), another cardiology mainstay, went off patent, though it wasn’t until earlier this month that multiple generics became available.

The FDA said that it had approved 300 mg formulations of clopdiogrel from Gate Pharmaceuticals, Mylan Pharmaceuticals, and Teva Pharmaceuticals and 75 mg formulations from Apotex Corporation, Aurobindo Pharma, Mylan Pharmaceuticals, Roxane Laboratories, Sun Pharma, Teva Pharmaceuticals, and Torrent Pharmaceuticals.

In recent years the FDA approved two newer antiplatelet drugs that had been designed to take over the central role of Plavix in treating acute coronary syndromes. However, these drugs, prasugrel (Effient) and ticagrelor (Brilinta) have been struggling in the marketplace, and at this point appear very unlikely to command a significant share of the market.
Click here to read the FDA press release…

Failure of Another Trial Testing Guided Antiplatelet Therapy Prompts Debate 4

Updated, Saturday, April 7

Yet another trial has failed to prove the hypothesis that guided antiplatelet therapy with platelet function testing or genetic testing improves outcomes. Although there has been no public announcement so far, the TARGET-PCI (Thrombocyte Activity Reassessment and GEnoTyping for PCI) was suspended last October, according to the TARGET-PCI page on ClinicalTrials.Gov.

TARGET-PCI was a large study in which 1,500 PCI patients were randomized to guided antiplatelet therapy with genotyping and platelet function tests or standard antiplatelet therapy. The primary endpoint was major adverse cardiovascular events at 6 months. The principal investigator was Paul Gurbel of Sinai Hospital of Baltimore, where the study was performed.

Here is what one cardiologist who wished to remain anonymous commented about the trial:

It was an ambitious study that was probably underpowered to look at efficacy outcomes. The positive predictive value of the CYP2C19*2 allele is reported as being < 20%. My guess is that the study was halted due to futility, and they discovered that it would be unlikely that any difference in outcome would be apparent with either personalized guided therapy or with routine care, even if the study was carried to completion.

This mirrors what we saw with the TRIGGER-PCI study and GRAVITAS, with the addition of the genetic testing by the Verigene assay.   It seems that both the Verify-now and Verigene assays are solutions still looking for problems to solve.

Sanjay Kaul offered the following comment:

The prognostic utility for genotype testing is not substantial or consistent. The outcome most strongly associated with CYP2C19 loss of function genotype is stent thrombosis (hazard ratio of 3 to 4), a rare but potentially life-threatening event. However, given the rare occurrence of stent thrombosis, the positive predictive value of genotype is only 3-4%, too small to be clinically directive. A randomized controlled trial to definitively address the role of genotype is currently lacking. Given the paucity of thrombotic events, a trial with a sample size of 20,000-30,000 would be required to adjudicate the clinical utility of genotype testing, a number that might be understandably viewed as being prohibitive. With a sample size of around 1500 and a follow-up up to 6 months, the TARGET-PCI is woefully underpowered to address this. Not surprisingly, and given the null results of GRAVITAS and premature stopping of TRIGGER-PCI for futility, the decision to suspend TARGET-PCI does not seem unwarranted.

Based on the totality of evidence, personalized antiplatelet therapy using genotype testing cannot be routinely recommended at the present time. The CYP2C19 polymorphisms affecting clopidogrel metabolism offers a cautionary tale about the unlimited power of genetic technology to generate ‘bountiful’ information on one hand, and our limited ability to properly analyze, reliably interpret, and judiciously translate it into clinical practice on the other hand. The CYP2C19 polymorphisms were heralded with much fanfare to catapult genomics to prominence in personalized cardiovascular medicine. However, the cold hard facts are that not only is the use of genetic testing to improve risk stratification premature, but whether the power of genomics can be harnessed to improve decision making and clinical outcomes also remains to be defined. The unbridled (and uncritical) enthusiasm for genomics revolutionizing personalized medicine has often blurred the distinction between hope, hype and reality. While the progress in DNA sequencing technology and bioinformatics is undeniably breathtaking, the translation of this knowledge to clinical practice has lagged behind. Genomics will eventually get there, but it cannot be expected to move faster than the speed of science.

Eric Topol offered this response to Kaul’s statement:

With at least 30% of individuals carrying DNA loss-of-function sequence variants for metabolizing clopidogrel, it should be standard of care to genotype individuals who are undergoing coronary stenting. The recent RAPID GENE publication in the Lancet (from last week), the first randomized trial of rapid, point of care genotyping , demonstrated unequivocal and marked improvement in platelet suppression using genotype-guided information as compared with no DNA data. The resistance to use genomic data to improve patient care is indefensible, and does not require “a trial with a sample size of 20,000-30,000 would be required to adjudicate the clinical utility of genotype testing.” That trial will never be done, is not even warranted, and while the debate for its need ensues, too many patients will experience stent thrombosis unnecessarily. And the stakes are high, since most stent thrombosis results in MI or death. In next week’s JAMA correspondence, there will be important perspectives published on this matter.

Update, Saturday, April 7:  Sanjay Kaul provided the following response to Topol’s statement. CardioBrief has invited Topol to respond:

The message I take away from the RAPID GENE trial is that point-of-care genetic testing is clinically feasible and might facilitate rapid personalization of anti-platelet therapy. However, genomic data is best utilized to “improve patient care”, not to “improve platelet suppression” – a surrogate marker of unclear clinical relevance. Although the trial was not powered to address clinical outcomes, bleeding episodes occurred in 5/91 of the rapid genotyping patients compared with 2/96 of standard therapy patients.

Individualizing antiplatelet therapy should ideally be based on a biomarker that precisely measures drug responsiveness, accurately characterizes low and high risk patients, is readily available and affordable, and reliably guides treatment decisions to optimize outcomes in a cost-effective manner. Unfortunately the quest for such a biomarker remains elusive as none of the currently available genetic tests (or platelet function tests) exhibits these desirable attributes.

Despite the inordinate attention being given to genomic and personalized medicine, the body of evidence continues to be insufficient to justify the clarion calls for “standard of care” use of genotype testing in the care of patients undergoing coronary stenting.

CardioBrief will be happy to provide a forum for additional discussion and debate about this topic.

Proof-of-Concept for Bedside Rapid Genotyping Test of CYP2C19 1

A new point-of-care test can rapidly identify people with a common genetic variant associated with impaired clopidogrel function. The authors claim that this is the first study to demonstrate the feasibility of delivering a genetic test at bedside.

In an article published online in the Lancet, Jason Roberts and colleagues report on a new point-of-care test that can identify people who have a common variant of the CYP2c19 gene associated with reduced clopidogrel effectiveness. In their “proof-of-concept” study, 200 patients undergoing PCI were randomized to standard therapy with clopidogrel or to the new test. Patients found to have the CYP2C19*2 allele received prasugrel instead of clopidogrel.

Each group had 23 patients who carried at least one CYP2C19*2 allele. Among these patients, no patients in the test group, and 7 patients (30%) in the control group, were found to have high on-treatment platelet reactivity (PRU) after 1 week of treatment. At 7 and 30 days, there were no ischemic events in either group and no significant differences in major or minor bleeding.

The investigators write that their study “confirms the potential clinical benefits associated with a personalised approach to antiplatelet treatment with selective use of P2Y12 inhibitors in patients at increased risk of adverse events with clopidogrel,” but they also noted that the “major limitation” of their study “was use of a surrogate endpoint to assess clinical efficacy.”

In an accompanying comment, Amber L Beitelshees notes that “.”many clinicians do not know what action to take, if any” until the completion of large trials that are in progress. Earlier studies testing the platelet hypothesis may have failed, she says, because new evidence suggests that benefits of genotyping or platelet function tests may be confined to the PCI population. The new rapid genotyping test will make it easier “for incorporation into clinical care in the catheterisation laboratory.”
Click here to read the Lancet press release…