FDA Reviewers Deliver Split Opinion On The Medicines Company’s Cangrelor Reply

FDA reviewers presented two dramatically different views of The Medicines Company’s investigational new drug cangrelor. One reviewer says the drug should not be approved without a new trial and even states that the CHAMPION trials “were conducted unethically” and should not be approved “on that fact alone.”  But two other reviewers recommend approval.

Click here to read the full post on Forbes.

 

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Prolonged Dual Antiplatelet Therapy May Not Be Necessary For Second-Generation Drug-Eluting Stents Reply

The precise duration of dual antiplatelet therapy (DAPT) following implantation of a drug-eluting stent (DES) has been the subject of considerable controversy. On the one hand, prolonged therapy may help prevent late stent thrombosis, which was particularly evident in first generation DESs. On the other hand, the risk of stent thrombosis may have diminished in newer generation drug-eluting stents, and prolonged DAPT  is associated with a greater risk for bleeding complications and additional expense and management issues.

In the Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice (OPTIMIZE) trial 3,119 patients with stable CAD or a history of low-risk acute ACS who received a zotarolimus-eluting stent (Endeavor, Medtronic) were randomized to either short-term (3 months) or long-term (12 months)  DAPT. The results of OPTIMIZE were presented at TCT 2013 in San Francisco and published online in JAMA.

At one year there were no significant differences between the groups. The primary endpoint– the composite of death, MI, stroke, or major bleeding– occurred in 6% of patients in the short term group versus 5.8% of patients in the long-term group (risk difference 0.17, CI -1.52 – 1.86, p = 0.002 for noninferiority). Between 3 months and 1 year there was an identical 2.6% rate of events in both groups.

Click here to read the full post on Forbes.

 

ARCTIC Blows A Cold Wind On Platelet Function Tests 1

The use of platelet-function tests to monitor and guide antiplatelet therapy in PCI patients has sparked heated debate. Cardiologists have sought to reconcile biological plausibility with the absence of clinical evidence. Now the ARCTIC (Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a Monitoring-guided Strategy for Drug-Eluting Stent Implantation versus Continuation One Year after Stenting) trial brings cold comfort to supporters of the monitoring strategy.

The ARCTIC investigators randomized 2440 PCI patients either to a strategy in which antiplatelet therapy was guided by platelet-function monitoring, or to conventional therapy without monitoring. The VerifyNow P2Y12 and aspirin point-of-care assay was used in the monitoring group. Results of the trial were presented at the American Heart Association scientific sessions in Los Angeles on Sunday and published simultaneously in the New England Journal of Medicine.

The primary endpoint was the composite of death, MI, stent thrombosis, stroke, or urgent revascularization at 1 year:

  • 31.1% in the conventional group and 34.6% in the monitoring group (HR 1.13, CI 0.98-1.29, p=0.10)

The ARCTIC investigators also reported a main secondary endpoint consisting of stent thrombosis, revascularized or not, or any urgent revascularization:

  • 4.6% and 4.9% (HR 1.06, CI 0.74-1.52, p=0.77)

In the monitoring group, 7.6% of patients were found to be poor responders to aspirin and 34.5% were poor responders to clopidogrel. The authors conclude that platelet-function testing with antiplatelet therapy adjustment does not improve clinical outcomes as compared with standard treatment and that their results “do not support the routine use of platelet-function testing in patients undergoing coronary stenting.”

A second arm of the trial, studying whether clopidogrel therapy should be continued after 1 year, is ongoing. In addition, a follow-up study, ANTARCTIC, is evaluating the value of platelet-function testing in an elderly population “with a paradigm shift towards safety.”

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…

The Return Of Vorapaxar, This Time For Post-MI Patients Reply

The once highly-promising novel antiplatelet agent vorapaxar, widely thought to be dead on arrival after unacceptably high serious bleeding rates were found in two large clinical trials, has now returned to active duty. On Sunday the drug’s sponsor, Merck, announced that it would seek approval of the drug, with a narrower indication than originally planned, based on new data from a prespecified analysis of the TRA 2P-TIMI 50 trial presented at the ESC and published simultaneously in the Lancet.

Merck said it planned to file applications next year in the United States and Europe for an indication for the prevention of CV events in patients with a history of MI and no history or stroke or TIA.

The new hope for the drug is based on an analysis of the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events trial, which was originally presented in March at the ACC and published simultaneously in the New England Journal of Medicine. In the overall trial, which randomized 26,449 patients with a history of MI, ischemic stroke, or peripheral arterial disease to either vorapaxar or placebo in addition to standard therapy, the rate of CV death, MI, or stroke was significantly reduced by vorapaxar, but a doubling of the rate of intracranial bleeding left many convinced the drug was not commercially viable.

The new analysis, presented at the ESC by Ben Scirica,  focused on the subgroup of 17,779 TRA 2P patients– a group larger than usually found in the entire population of most clinical trials, it should be noted– with a history of myocardial infarction. After 2.5 years of followup, the rate of CV death, MI, or stroke was significantly reduced in the vorapaxar group compared to the placebo group, though vorapaxar was also associated with an increased risk of bleeding, but not intracranial bleeding:

  • Primary endpoint: 8.1% versus 9.7%, HR 0.80, CI 0.72-0.89, p<0.0001
  • Moderate or severe bleeding:3.4% versus 2.1%, HR 1.61, CI 1.31-1.97, p<0.0001
  • Intracranial hemorrhage: 0.6% versus 0.4%, p=0.076

The authors acknowledged the limitations of subgroup analysis but proposed that vorapaxar might be beneficial in a population with a history of MI but with no history of stroke or TIA, age below 75, and weight over 60 kg.

In an accompanying comment in the Lancet, Stefan James and Claes Held write that the “results support the addition of long-term antithrombotic treatment for patients who have had a myocardial infarction.” But, they ask, “will doctors, patients, health-care providers, and funding agencies accept use of an expensive drug to reduce the risk of myocardial infarction and possibly death in view of the increased risk of severe bleeding?”

Republished with permission from CardioExchange, a NEJM group publication.
Click here to read the Lancet 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.