So Long, Plavix, What a Ride! Clopidogrel Patent Expires

May 17, 2012

May 16, 2012 (Hamilton, Ontario)— For years it was the second-best selling drug in the world, with more than $9 billion in global sales in 2010 alone, but the golden era of a patented clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi) is drawing to a close. Like atorvastatin, which for years held the global crown as the most widely prescribed drug, clopidogrel will be available to patients as a generic drug as of May 17, 2012.

Mid-afternoon on May 17, the Food and Drug Administration (FDA) announced it had approved 300-mg doses of generic clopidogrel made by three generic companies and a 75-mg dose made by seven companies.

Approved by the FDA on the basis of the CAPRIE trial in 1997, a study that tested the antiplatelet agent against aspirin for the reduction of cardiovascular events in patients with recent stroke, MI, or peripheral artery disease, the indications for clopidogrel have continued to expand over the years. That widening reach has come to include patients with acute coronary syndromes (ACS), including non-ST-segment-elevation MI (NSTEMI) and STEMI patients, as well as in combination with aspirin in patients treated with a coronary stent.

Clopidogrel is a drug of "major historical significance," said Dr Thomas Tu (Louisville Cardiology Group, KY), noting that clopidogrel was the first agent shown in a variety of patients to reduce the risk of MI and mortality when added to aspirin therapy. He highlighted its early role, telling heartwire that researchers and clinicians were initially seeking a "better aspirin" for the treatment of patients with coronary artery disease.

"To understand clopidogrel, you have to really go back to the early years of cardiology," said Tu. "In the time before clopidogrel, we were really looking for new treatments for patients with cardiovascular disease. Twenty years ago, the mortality from myocardial infarction was much higher than it is today. Aspirin had already been discovered as an antiplatelet agent that could reduce mortality from myocardial infarction, and we thought that this was mediated through its antiplatelet effect."

Prior to clopidogrel, clinicians had tried various drugs, including anticoagulants, to reduce the risk of death following myocardial infarction, but to no avail.

"It seems counterintuitive in the modern era, but back then we thought that myocardial infarction was a thrombotic disease, so we thought we'd be able to give an anticoagulant to save people's lives or to reduce the severity of their infarct," Tu told heartwire . "What we found was that we made people bleed but we didn't actually improve their outcomes at all. Clopidogrel, other than aspirin, was really the first agent that could thin the blood and save lives over the long term."

Throwing the Kitchen Sink at Stented Patients

While CAPRIE saw the emergence of clopidogrel, it took some time before researchers and clinicians found the "sweet spot" with the antiplatelet--its use in combination with aspirin following PCI in the CREDO trial. Dr Eric Topol (Scripps Clinic, La Jolla, CA), who was on the CAPRIE steering committee and chaired the CREDO steering committee, told heartwire that the study remains the most cited paper in his entire career, with 2238 citations in the medical literature as of April 2012. He added that more than two million people receive a stent each year and clopidogrel plus aspirin remains the standard of care.

"I think it's had an enormous impact in the coronary intervention/stent world over the years," Topol told heartwire . "I was involved with clopidogrel with the first-in-man studies back in the 1980s, which makes me feel very old, but back then stents were just coming into play, and we didn't realize what would be the best treatment regimen. While clopidogrel was being tested in the first-in-man studies, we were giving everything but the kitchen sink to stented patients, including Coumadin [warfarin] and dextran. Everything but clopidogrel."

Dr Robert Harrington (Duke Clinical Research Institute, Durham, NC) said it is difficult to discern an "aha" moment with clopidogrel, where physicians knew that dual antiplatelet therapy with aspirin was going to change clinical practice. The clinical events stent thrombosis and MI, for example, are relatively infrequent, so physicians really had no idea how large a role clopidogrel was going to play. One of the major benefits of treating patients with aspirin and clopidogrel was apparent in how quickly stented patients could move out of the hospital, however.

"When stents first came onto the scene in the US, they were largely used as bailout as opposed to stenting right away," he told heartwire . "In the days when we first starting putting stents in at Duke, the antithrombotic regimen was extensive--it was dextran, it was dipyridamole, aspirin, huge doses of heparin, and then we would transition patients to warfarin when trying to take the sheaths out of patients who were massively anticoagulated. Back in the early days of stenting at Duke, the length of stay for patients was six days."

Dr Jeffrey Marshall (Northeast Georgia Medical Center, Gainesville), the president-elect of the Society for Cardiovascular Angiography and Interventions (SCAI), said the preclopidogrel era saw "tremendous bleeding issues" with patients undergoing PCI, especially as patients were switched from heparin to warfarin.

"The first stents were quite large and required large-bore groin sheaths, so the bleeding complications were just enormous," he told heartwire . "Understanding the importance of dual antiplatelet therapy with clopidogrel was a great advance forward over Coumadin and even over ticlopidine. It was a great advantage to get a once-a-day drug and to get away from the bleeding that Coumadin caused. The bleeding with full heparinization and Coumadin for the first coronary stents makes the bleeding with clopidogrel seem like a walk in the park."

It was a beautiful story and clearly altered the way we think.

Harrington credits Dr Martin Leon (Columbia University, New York) and the STARSinvestigators for their observation that ticlopidine plus aspirin was superior to aspirin plus warfarin, a study that paved the way for dual antiplatelet therapy in stented patients. From there, clopidogrel emerged as researchers began to look for a replacement for ticlopidine, a drug that wasn't particularly well tolerated by patients. Dr Paul Gurbel (Sinai Hospital of Baltimore, MD) noted that early work done in animal and ex vivo models with clopidogrel showed that adding it to aspirin enhanced the antithrombotic effect, and this work directly translated into improvements in clinical outcomes in high-risk patients.

"It was a beautiful story and clearly altered the way we think to optimally treat patients who have high-risk cardiovascular disease," Gurbel told heartwire . "It revolutionized what we do in cardiovascular medicine, whether we treat acute coronary syndromes or non-STEMI or STEMI patients. It's standard of care to give dual antiplatelet therapy."

Goodbye Plavix, Hello Clopidogrel

With clopidogrel now available as a generic medication, many expect the antiplatelet to continue to play a role in cardiovascular care, especially since branded Plavix may have been cost-prohibitive in patients without health insurance. This often led to patients discontinuing their clopidogrel early, which in turn put them at risk for thrombotic events.

"Cost was a major barrier for longer-term use of clopidogrel in some patients," Dr Shamir Mehta (McMaster University, Hamilton, ON) told heartwire . "So now that it is generic, there will likely be an increase in compliance with long-term therapy. I think in any population where there are going to be affordability issues, clopidogrel will still be used."

Mehta, one of the investigators of the CURE trial that led to the approval of clopidogrel plus aspirin in patients with ACS-NSTEMI, said it is hard to predict how quickly clopidogrel will disappear from regular use given the approval of other agents, some of which have shown superiority to clopidogrel in certain settings, such as prasugrel (Efient, Lilly/Daiichi Sankyo) in the TRITON-TIMI 38 trial of ACS patients scheduled for PCI (albeit with an increased risk of bleeding) or ticagrelor (Brilinta, AstraZeneca) in the PLATO trial.

"Clopidogrel is a drug that is widely used across the spectrum of acute coronary syndromes, in patients undergoing PCI, in patients who have had a [transient ischemic attack] TIA or stroke, and in patients with peripheral arterial disease, and it's used as an alternative to aspirin for secondary prevention," said Mehta. "So its use is widespread across multiple indications. Any time you have a drug that is that widely used, any changes in practice are going to be slow to occur when a drug goes off patent."

Harrington agreed. "Around the globe, depending on what the cost constraints are, it's a very good drug," he said. "Doctors might also choose to use clopidogrel in other settings where the newer drugs have yet to be proven to be effective." He added that that in an emerging era of understanding optimal or target levels of platelet inhibition, different agents might be selected for different patients. "It could be that whatever drug gets you there [to optimal platelet inhibition]: that's the one you use."

To heartwire , Marshall cautioned that the costs of the generic drug will be more than a couple of dollars a month and likely won't be a whole lot less expensive if it is marked up by the pharmacies dispensing it. But regardless of what the cost turns out to be, it will be cheaper than the branded version, and it's already on the radar of patients who are asking about its availability, said Marshall.

Praise for the Company

One of the reasons why there are a wide variety of uses for clopidogrel is that the company continued to test the agent in different clinical settings. CAPRIE, CREDO, and CURE were followed by expanded indications for use in patients with acute STEMI based on the COMMIT and CLARITY trials. In addition to successes in a variety of ACS and postprocedural settings, the drug has continued to be studied throughout its entire lifespan.

"What's impressed me about clopidogrel is that the company didn't just do the typical postmarketing stuff--small trials that they could have easily disassociated themselves from if they didn't like the answer," Harrington told heartwire . "They really chose to do, time after time, large important studies trying to better understand if the drug could be used in new indications, if it should be used in different doses, if it should be used for longer periods of time. For me, that's probably the most important message from the clopidogrel story."

Mehta agreed with the assessment. "The companies were not afraid to take certain risks in testing the drug in new indications," he said. "Although they had enormous success, they also had their share of failures.  From our point of view as physicians, the value of these trials is that we have a pretty good idea of where clopidogrel is effective and safe and where it is not."

One of those negative studies was CHARISMA, a large study of 15 603 patients with clinically relevant cardiovascular disease or multiple risk factors randomized to clopidogrel 75 mg/day plus low-dose aspirin or placebo plus low-dose aspirin. The study included a mix of approximately 3000 primary-prevention patients and 12 000 symptomatic secondary-prevention patients. Overall, the study was negative, but investigators noted that the drug appeared to reduce the risk of MI, stroke, or death from cardiovascular causes in the secondary-prevention cohort but increased the risk of cardiovascular events, particularly cardiovascular death, in the primary-prevention group. This led investigators to conclude that dual antiplatelet therapy should not be used in patients without a history of established vascular disease.

Topol, the senior investigator of CHARISMA, called the results a bit of a "shock" but said it helped clinicians identify the "wall" with clopidogrel. He told heartwire that over time researchers have come to learn that primary prevention with antiplatelets, including aspirin, is a very tricky area.

Speaking with heartwire , Dr John Tsai, vice president of US medical at Bristol-Myers Squibb, said that clopidogrel has benefited more than 115 million patients worldwide, including 50 million in the US. He said the research and development conducted by the company has been part of its philosophy to understand the broadest possible area in which clopidogrel can have an impact on patient's lives. For him, he sees clopidogrel's largest benefit in the ACS setting, including STEMI and NSTEMI patients, simply given the size of this patient population.

"It would be ideal if all trials came out positive, but these are the research questions we have when we conduct clinical trials," said Tsai. "There were a couple of trials that came out neutral, neutral in the sense that they didn't show as much benefit as we were hoping for, including the CHARISMA study. That's part of clinical-trial work."

Patent Up, But More Questions Still Remain

Clinical trials have not, however, provided all the answers. In fact, the emergence of platelet-function testing and genotyping for CYP2C19 has only led to more questions about who should take the drug and for how long. In recent years, there has been recognition that patients with common loss-of-function CYP2C19 alleles were at a significantly increased risk of stent thrombosis when treated with clopidogrel.

Topol believes platelet-function testing or genotyping should be performed in most patients who receive a coronary stent, especially since nearly one in three patients cannot metabolize clopidogrel. While one loss-of-function allele might be compensated by doubling the dose of clopidogrel, having both CYP2C19 loss-of-function alleles all but ensures these patients will be unable to convert clopidogrel to its active form.

"You'd think that knowing that one-third of patients don't have a good response to clopidogrel we'd see a change in practice based on all the data that exist today," Topol told heartwire . "I'm not a fan of surrogate end points, but platelet suppression here is a reasonable proxy for whether or not you are inhibiting the platelets."

In addition, there remains uncertainty in terms of how long patients should be treated with dual antiplatelet therapy following implantation of a drug-eluting stent. Some studies have suggested it is safe to stop clopidogrel after six to 12 months, but others advocate for larger clinical-outcome studies such as the Dual Antiplatelet Therapy (DAPT) trial before making firm conclusions.

Things are likely to be very different in the next decade.

To heartwire , Gurbel said he expects dual antiplatelet therapy in the future to be determined less by a "willy-nilly" absolute cut point but instead by the patient's thrombotic physiology using platelet-function or genetic testing. In the early days, he said, his research group had numerous studies on clopidogrel resistance rejected by the American College of Cardiology, American Heart Association, and European Society of Cardiology meetings because physicians did not believe there was any such thing. Today, the Scripps Clinic routinely offers patients undergoing elective stenting a test for the gene variants associated with an inability to convert clopidogrel to its active metabolite, and Vanderbilt University Medical Center, taking this a step further, has said it will test all patients likely to receive antiplatelet therapy sometime in the future.

"With a generic clopidogrel, there will be an impetus to personalize the antiplatelet therapy,” said Gurbel. " 'If the patient responds to clopidogrel, then why prescribe the more expensive drug?' some might say. 'If they respond to it, then why not use a drug that is cheap?' That's what people who are paying the bills are going to be thinking."

Future studies with clopidogrel are highly unlikely to be sponsored by Bristol-Myers Squibb or Sanofi, but that doesn't mean they won't be done, according to the experts. Some envision a role for the National Institutes of Health (NIH), with the agency possibly interested in establishing the cost-efficacy of different treatment strategies, while other drug companies might be interested in putting their drugs up against clopidogrel, the longstanding standard of care.

"It's been a very exciting time, but we're now moving into a new era with newer drugs that overcome some of the limitations of clopidogrel," said Mehta. "We are also learning more about genetic polymorphisms in enzymes that metabolize the drug. Things are likely to be very different in the next decade."

Tu noted that while the early hunt for a "better aspirin" focused on platelets rather than the clotting cascade as the real ticket to treating coronary artery disease, the field has now come full circle with the development of anticoagulants for ACS, such as rivaroxaban (Xarelto, Bayer/Johnson & Johnson). In the ATLAS ACS 2-TIMI 51trial, rivaroxaban reduced the risk of overall and cardiovascular mortality when compared against placebo. FDA advisors will be reviewing the company's bid to expand the indication for rivaroxaban into an ACS population, based on ATLAS ACS, at an advisory committee meeting one week from today.

"This year is kind of the swan song for clopidogrel as a branded drug and now it opens the door to a whole new era," he said. "Now we're going to be experimenting with all these antithrombotic agents in addition to what we've learned from dual antiplatelet therapy."

Topol is the editor-in-chief of theheart.org and reports no conflicts of interest. Harrington reports consulting or non–continuing-medical-education (CME) services for Bristol-Myers Squibb, Pfizer, Cortex, CSL Behring, Daiichi Sankyo, Eisai, Genentech, Gilead, Johnson & Johnson, Janssen, Orexigen, Regado Biosciences, Sanofi, and WebMD/theheart.org. He also reports consulting and CME services for WebMD/theheart.org and research grants from Sanofi, Portola Pharmaceuticals, Merck, GlaxoSmithKline, CSL Behring, and Bristol-Myers Squibb. Gurbel reports research grants/support from Pozen, AstraZeneca, Nanosphere, Accumetrics, Helena, Multiplate, Portola, and Daiichi Sankyo. In addition, Gurbel has received honoraria/consulting fees from Pozen, Novartis, Bayer, AstraZeneca, Eli Lilly, Accumetrics, Nanosphere, Sanofi, Boehringer Ingelheim, Merck, Medtronic, and Iverson Genetics. He also holds patents in the field of platelet-function testing. Mehta reports consulting for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Sanofi. Tsai is an employee with Bristol-Myers Squibb. Tu reports no conflicts of interest. Marshall reports grant research support from Corindas, Abbott, Medtronic, Lilly, Daiichi-Sankyo, Schering-Plough, Sanofi, St Jude, and Boston Scientific. He serves on an advisory board/speaker's bureau for the American Board of Internal Medicine and Abbott.

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