Recently in Cardiology Category
The FDA has revised its recommendations for cardiovascular monitoring after the initiation of Gilenya (fingolimod), Novartis's oral drug for relapsing-remitting MS. The new recommendations, which extend the post-dosage monitoring for bradycardia from 6 to 24 hours, are based on the report of a woman who died within a day after starting the drug. Although the cause of the woman's death was not determined, the agency reported that she was taking two antihypertensive medications, including the beta-blocker metoprolol. In addition, she had "extensive" MS lesions in her brainstem, which have been associated with sudden death.
On the basis of a post-hoc analysis of clinical-trial data, the FDA also concluded that the possible depressant effect of Gilenya on the heart rate is biphasic: There is an initial risk during the first 6 hours after the first dose and a second risk during hours 12-20. Therefore the agency believes that cardiac monitoring beyond 6 hours is warranted in patients whose heart rate falls below 45 bpm during the first 6 hours after the first dose.
Other reports of cardiovascular death in Gilenya-treated patients are being examined. However, the FDA cautions, "For each of these deaths, Gilenya’s contribution to the death was unclear. The number of deaths of apparent cardiovascular origin or of unknown origin does not appear to be higher than in MS patients not treated with Gilenya."
Regardless it seems prudent to consider the drug very carefully in MS patients with concomitant cardiovascular disease (especially arrhythmia) and particularly those patients taking beta-blockers or antiarrhythmics.
Yesterday the FDA announced that it will evaluate postmarketing reports of "serious" bleeding in patients taking the anticoagulant Pradaxa (dabigatran); although the agency doesn't say how many reports of serious bleeding have been received since the drug was approved a little more than a year ago.* The FDA is basing its analysis on data from its own pilot program, the Mini-Sentinel system, as well as submitted information to its standard reporting system, AERS. Currently Pradaxa is only available in the United States in the form of 150- and 75-mg pills, the latter approved for renally compromised patients (CrCL 15-30 mL/min) and solely on the basis of pharmacokinetic studies. The FDA has been criticized for failing to approve the 110-mg pill, which was shown to be comparable (ie, nonsuperior) to warfarin in the large RE-LY trial (for background, start here). According to SDI's proprietary national tracking services, cited by the FDA, about 1.1 million prescriptions for Pradaxa were dispensed in the United States between October 2010 and August 2011, and 371,000 patients received Pradaxa from outpatient retail pharmacies. Not a huge population, but not insignificant either.
The FDA also advises, wisely, that comparing postmarketing reports of bleeding with Pradaxa and those with warfarin is probably not helpful, because "warfarin has been marketed for over 50 years and is well known to cause bleeding, [consequently] patients and healthcare professionals are not likely to report bleeding in association with warfarin." The agency concludes, "Thus, a simple comparison between Pradaxa and warfarin...is of limited value." The FDA also says that it's working with Pradaxa's manufacturer, Boehringer Ingelheim, to assess a range of potentially adverse postmarketing events.
AERS = Adverse Events Reporting System.
* For the prevention of stroke and other cases of systemic embolism in patients with nonvalvular a-fib.
Today marks the generic availability of Pfizer's Lipitor, the blockbuster drug to beat all blockbuster drugs.Duff Wilson of the NYT lays out how Pfizer is leveraging its short-term losses (for instance, it will get 70% of generic maker Watson's profits).
And Forbes's Matthew Herper gets nostalgic for the era of the widely prescribed money maker ("Why There Will Never Be Another Drug Like Lipitor"). Specifically he provides a concise history of Lipitor's rise and plateau; but he unfortunately omits one of the most interesting and important points of the early Lipitor campaign.
When first approved by the FDA in 1996, Lipitor was only indicated to reduce LDL cholesterol; it had not been shown to prevent clinical vascular events like its 4 existing statin competitors at the time. Nevertheless, trial data showed that Lipitor reduced LDL cholesterol by a relatively greater percentage than the other statins. And because clinicians believed (and still do) that LDL cholesterol is directly linked to the risk of vascular events, Pfizer was able to leverage this belief into ever-escalating sales during the next several years without having data to show that Lipitor actually reduced the risk of vascular events.* Clinicians made the a-to-b-to-c connection with prescription-writing alacrity.
Oh BTW, the generic name of Lipitor: atorvastatin.
* Lipitor wasn't approved by the FDA for this indication until 2004.
Delayed update (12/10/11): In an intriguing NEJM Perspective piece, Jackevicius et al expect that atorvastatin will "dominate" the statin market as a result of switching from generic simvastatin and branded Crestor. Specifically, in 3 years, they expect the market share of atorvastatin to reach 44%. They also estimate, on the basis of experience with simvastatin (which went generic in 2006), that the price of generic atorvastatin will be about 50% of the price of branded Lipitor, after the 6-month exclusivity period ends for the first generic manufacturer.
The projected overall cost savings by 2014, owing to the generic availability of atorvastatin: $4.5 billion annually; when factoring in the aging of the population, add another $30 million. These projections assume the "rapid availability and timely uptake of generic atorvastatin," which may be delayed thanks to industry maneuvers between Pfizer and generic drug makers (which are designed to limit competition). Pfizer is also reportedly planning to ask the FDA to approve an OTC version of Lipitor at some unspecified date.
Xarelto is the second anticoagulant to seriously compete with the old-as-dirt warfarin for the prevention of stroke in patients with a-fib. In October of last year, the FDA approved Boehringer Ingelheim's Pradaxa (dabigatran), a direct thrombin inhibitor. Neither medication requires the usually cumbersome protime monitoring, but Pradaxa, unlike Xarelto, was shown to be superior (at the 150-mg BID dosage) to warfarin for the prevention of stroke in a similar patient population.
Other important differences between Xarelto and Pradaxa are 1) the package insert for the former contains a so-called black-box warning (against the risks of thrombosis after drug discontinuation and spinal/epidural hematoma); and 2) Xarelto is taken once a day, unlike the twice-daily Pradaxa.
Beyond superior-versus-noninferiority claims, potential drug-related risks, and any convenience of dosing, a distinction between Xarelto and Pradaxa may emerge with respect to pricing. According to destinationrx, a month's supply of Xarelto costs $218.70 (~$7.30 per pill or day).** A month's supply of Pradaxa (60, 150-mg pills) will set you back $236.20 (~$7.87 per day). Much of the cost distinction between these 2 drugs, however, will probably depend on how formularies classify the drugs and exact prescription co-pays on health-plan members. Branded warfarin (ie, Coumadin) is, of course, a fraction of these costs, and the price of generic warfarin (which some cardiologists are loathe to prescribe owing to the unpredictability of protimes) is even lower still.
* As well as for the prevention of deep vein thrombosis (DVT).
** 10 mg daily is the dosage for DVT prophylaxis; for the prevention of stroke in patients without renal dysfunction, the recommended dosage is 20 mg per day.
In a company press release, issued July 4th,* Pfizer said it "stands behind the benefit/risk profile of Chantix" and "expressed concerns about the reliability of the meta-analysis." Specific concerns related to the "appropriateness of the authors' measure of cardiovascular risk...which combines events that do not share a common biological cause." The probable main objection here is the inclusion of arrhythmias in the composite endpoint, which may not have anything to do with the process of vascular disease. Pfizer also stressed the small absolute difference between Chantix- and placebo-treated patients. The company reported that it plans to conduct its own meta-analysis to assess the potential cardiovascular risks of Chantix.
In June, the FDA posted a warning about the potential, albeit small, cardiovascular risks of Chantix. The warning was based on data from a 1-year, randomized, placebo-controlled trial of 700 smokers. Both the efficacy and safety results are tabulated here. Clearly Chantix improves the chances of quitting (which should lower tobacco-related cardiovascular and cancer risks—!), but short-term cardiovascular risks may also exist with use of the drug.
|
Outcome |
Chantix |
Placebo |
P Value |
|
Continuous
quit rate, % |
47 |
14 |
<.0001 |
|
Continuous abstinence rate, % (weeks 9-52) |
19 |
7 |
<.0001 |
|
Nonfatal MI, % |
2.0 |
0.9 |
Not calculated |
|
Need for coronary revascularization, % |
2.3 |
0.9 |
Not calculated |
|
Angina requiring hospitalization, % |
2.3 |
2.3 |
Not calculated |
|
New diagnosis of PVD or PVD procedure, % |
1.4 |
0.9 |
Not calculated |
Notably this trial was not powered to detect statistically significant differences in the safety analysis portion of the study. The FDA affirmed that, on the basis of these data, it was "requiring the manufacturer to conduct a large, combined analysis (meta-analysis) of randomized, placebo-controlled trials" to further define the potential, short-term cardiovascular risks of Chantix.
* No holiday for public relations.
|
Endpoint |
Warfarin, % |
Pradaxa |
Pradaxa |
P |
|
Major bleeding |
|
|
|
|
|
All ages |
3.57 |
2.87 |
3.31 |
.002* |
|
Age <75 |
3.04 |
1.89 |
2.12 |
— |
|
Age ≥75 |
4.37 |
4.43 |
5.10 |
<.001* |
|
Extracranial bleeding |
||||
|
Age <75 |
2.44 |
1.76 |
1.91 |
— |
|
Age ≥75 |
3.44 |
4.10 |
4.68 |
.001* |
|
Intracranial bleeding |
||||
|
Age <75 |
0.61 |
0.14 |
0.26 |
— |
|
Age ≥75 |
1.00 |
0.37 |
0.41 |
.28* |
* P for interaction.
Consequently the lead author of the analysis, Eikelboom, concludes to heartwire that these new data "support the need for both doses of dabigatran to be made available in the US. The 150-mg dose will be the dose of choice in the under-75s but in older patients clinicians will want to consider the 110-mg dose to reduce the risk of extracranial bleeding."
In October of last year, the FDA approved only the 150-mg bid dosage of Pradaxa, and the agency attempted to justify its perplexing decision by providing a not-terribly-convincing argument in an April issue of the NEJM. Beasley et al rationalized that the FDA approval "was based on our inability to identify any subgroup in which use of the lower dose [110 mg bid] would not represent a substantial disadvantage." However, Eikelboom's subanalysis provides a compelling reason for approving the lower dosage (which is already available in Canada) in the United States.
Heartfelt blogger Melissa Walton-Shirley, a cardiologist, offers important experiential praise and criticism of Pradaxa (in contradistinction to my paper-based and generally unwavering praise of the drug).
Turns out that one of the potential downsides of the pill is, in fact, one of its biggest assets: freedom from warfarin-like drug monitoring. It seems that the idea of periodically testing and monitoring an anticoagulant's effect has been so engrained in the practice of medicine (and specifically cardiology) that physicians actually miss the tangible feedback. Who knew? This issue becomes a particularly touchy one when providing anticoagulation to the potentially renally compromised elderly—at least according to Walton-Shirley and a few commenters.
Another area of practical hedging: when to discontinue Pradaxa before surgery. Apparently surgeons are tap dancing on a recommendation that spans 3-5 days pre-op. As Walton-Shirley asks about this "gray zone": "Well, is it three or is it five?"
In November, BMS and Pfizer halted a large phase 3 study of their factor Xa inhibitor apixaban in patients with acute coronary syndrome (ACS), because of excess bleeding with the drug. It was a serious blow to the development program of a potentially viable alternative to existing, old-as-dirt anticoagulants, like heparin or warfarin. But the halted study, APPRAISE-2, was just 1 of 9 industry-sponsored trials assessing the potential benefits of apixaban in patients at risk of ischemic events. The companies were investigating the drug in other at-risk populations, like patients with a-fib or venous thromboembolism.
Now the highly favorable results of one of those studies, AVERROES, has been published in the NEJM.* In the double-blind study of 5599 patients with a-fib who were deemed unsuitable for warfarin therapy, apixaban (5 mg BID) reduced the risk of stroke by 55%, when compared with aspirin therapy (81-324 mg QD) at about 1 year (stroke rate, 1.6% vs 3.7%). There was also a statistical trend toward the reduction of death with apixaban (3.5% vs 4.4%; P = .07). Rates of major bleeding were nonsignificantly higher with the new agent (1.4% vs 1.2%). The number of intracranial bleeds were 11 with apixaban and 13 with aspirin. Apixaban may also provide some cardiovascular protection, as evidenced by the relative reduction of hospitalization for CV causes (12.6% vs 15.9%; P < .001).
The study, by design, may have been an easy score for BMS and Pfizer, because the comparator drug was aspirin in a population known to be at increased risk of stroke. But another study (ARISTOTLE) is comparing the investigational agent with standard-of-care warfarin. Study completion, according to clinicaltrials.gov, is expected in April.
ARISTOTLE = Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; AVERROES = Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment.
* The results were published ahead of schedule because the study was terminated early, in February of 2010, owing to the protective benefit of apixaban in patients with a-fib.
Horizontal CT image of massive, acute right hemispheric brain infarct with midline shift from Wikipedia.
Yesterday Merck announced major changes to 2 mammoth, placebo-controlled phase 3 trials of its novel antiplatelet agent,* which the company acquired by way of its famous merger with Schering-Plough. The use of vorapaxar,** specifically a thrombin-receptor antagonist, will be discontinued completely in the TRACER study, a hospital-based study of patients with acute coronary syndrome, and discontinued partly in the TRA-2P (or TIMI-50) study, a trial enrolling patients with prior MI, stroke, or peripheral artery disease. In the TRA-2P study, the drug will be stopped in stroke patients only, which make up about 25% of the study population, says the company's press release.
Reasons for the trial changes, which were made on the basis of a review by the Data and Safety Monitoring Board, are speculative; but the logical conclusion is that bleeding events were substantially greater in patients receiving the investigational drug. An article describing the TRA-2P study, published last year in the American Heart Journal by the TIMI Study Group, suggested that bleeding risks might be (relatively) reduced with varapaxar, because it "does not interfere with other pathways for hemostasis." (The standard, comparator antiplatelet would be aspirin, which acts fairly high up in the clotting cascade.)
Analysts' responses to Merck's news were cautious (which can be interpreted as extremely bearish). The company's share value was (probably overly) slammed on the news, by losing about 6% of its value.
Others are questioning whether the Merck-Schering merger was worth it, given the latest performance of this frontrunner compound—on which Merck (and others) placed high blockbuster-like hopes.
* Not to be confused with an anticoagulant and the developing market for this class of compounds.
** Aka SCH 530348.
01/20/11 update: In yesterday's press release, Merck reveals that, yes indeed, the reason that stroke patients are being removed from the TRA-2P study is because of an increased risk of hemorrhage—specifically an increased risk of intracranial hemorrhage. Patients with MI or peripheral vascular disease will continue on in the secondary-prevention* study of the company's novel antiplatelet agent.
According to the venerable Eugene Braunwald, Harvard cardiologist and chairman of the study, the Data and Safety Monitoring Board "observed an increase in intracranial hemorrhage in patients with a history of stroke that is not outweighed by their considerations of potential benefit."
Although TRA-2P is placebo controlled, all enrollees are receiving standard of preventive care in the form of aspirin or clopidogrel. The design of the trial is such that patients are undergoing (or underwent) randomization to treatment on the basis of their vascular disease and whether they were to receive clopidogrel. (So as far as I can tell, the study is one of really dual-antiplatelet therapy—in patients assigned to the investigational drug.)
* Or tertiary prevention, depending on how you define the term.
No. 4: Pradaxa—Drum Major for the Coming Anticoagulant Parade
In October, the FDA approved dabigatran (trade name, Pradaxa), the first drug to seriously challenge and potentially replace warfarin in the anticoagulant market. The direct thrombin inhibitor—developed by the private, German company Boehringer Ingelheim—is a potential uber-blockbuster, because it is a potential godsend for those patients with atrial fibrillation who would otherwise require warfarin to reduce the risk of stroke. Pradaxa's main advantage over the traditional anticoagulant: It does not necessitate laboratory monitoring (ie, protime measurements) and the consequent (and constant) adjustments of dosage.
On the basis of the huge RE-LY trial, the FDA approved Pradaxa at a dosage of 150 mg BID, which (when compared with warfarin) provided superior efficacy and comparable safety. An alternate dosage in the trial, 110 mg BID, was—curiously enough—not approved by the FDA, despite the fact that it showed comparable benefits to warfarin. Instead the agency gave a nod to a 75-mg alternative for renally compromised patients, on the basis of pharmacokinetic studies.
It's a regulatory decision that leaves many clinicians, save for cardiologist Sanjay Kaul, scratching their heads. In October, Kaul told told heartwire, "The 110-mg dose, while associated with reduced bleeding, had a 12% higher incidence of ischemic stroke. In my opinion, it would not offer much of an advantage over warfarin and would likely be an ineffective alternative."
But not allowing the 110-mg pill on the US market leaves Americans who don't respond reliably to warfarin and who can't tolerate the 150-mg BID dosage of Pradaxa with no reasonable options. In an effort to cater to these patients, some US physicians have been attempting to approximate the 110-mg BID dosage of Pradaxa by prescribing 75 mg TID; however, finding adequate pharmacy stocks of the 75-mg pill has been difficult, according to anecdotal reports. For some patients, this means returning to warfarin therapy and all its attendant frustrations—for the time being.
Pradaxa's FDA approval was followed, 1 month later, by the publication of a favorable, independent cost-effectiveness study—which showed that BI could justify asking up to $13.70 per day for its 150-mg BID regimen. But the company, in a show of fiscal responsibility, set a wholesale acquisition price at $6.75 per day, or $202.50 per month. The website destinationrx.com offers 60, 150-mg pills for $218.70.
The advent of Pradaxa may signify something more than just 1 option for warfarin-requiring patients. It may herald a Pharma resurgence, according to Forbes's Matthew Herper (The Medicine Show). Herper predicts that several emerging anticoagulants, along with Pradaxa, will likely replace warfarin altogether. Among these is Bayer Healthcare's Xaralto (rivaroxaban), a direct factor Xa inhibitor, which may be as good as or better than warfarin for preventing stroke in a-fib patients, according to clinical data presented in November at the American Heart Association meeting. Other promising, warfarin-shunning candidates in development include edoxaban (Daiichi Sankyo) and betrixiban (Merck).
However, one potential competitor, BMS/Pfizer's apixaban, recently hit a development brick wall. Excess bleeding in the APPRAISE-2 trial, a large phase 3 study of the factor Xa inhibitor (like Xarelto), led to a screeching halt of the trial. According to a joint company press release, "There was clear evidence of a clinically important increase in bleeding among patients randomized to apixaban. This increase in bleeding was not offset by clinically meaningful reductions in ischemic events."
But the APPRAISE-2 trial was just 1 of 9 trials assessing the potential benefits of apixaban in patients at risk of ischemic events. Other conditions in which apixaban continues to be investigated are a-fib and venous thromboembolism.
APPRAISE-2 = Apixaban for Prevention of Acute Ischemic Events-2; RE-LY = Randomized Evaluation of Long-term Anticoagulant Therapy.
* And despite the fact that it is approved in Europe and Canada.
