High platelet reactivity on clopidogrel predicts stent thrombosis, heart attack, and bleeding

Main Category: Cardiovascular / Cardiology
Also Included In: Medical Devices / Diagnostics;  Blood / Hematology
Article Date: 30 Jul 2013 - 0:00 PDT Current ratings for:
High platelet reactivity on clopidogrel predicts stent thrombosis, heart attack, and bleeding

Patients who receive a drug-eluting stent (DES) and demonstrate high platelet reactivity on clopidogrel are more likely to have blood clots form on the stent and to suffer a heart attack; however, these patients are less likely to develop bleeding complications. One-year results of the ADAPT-DES trial was published online in The Lancet. The findings were first presented at last year's Transcatheter Cardiovascular Therapeutics (TCT) annual scientific symposium.

ADAPT-DES is the largest study ever to explore the overall treatment implications of platelet reactivity on patient outcomes after successful coronary drug-eluting stent implantation. Researchers investigated the relationship between platelet reactivity during dual therapy with aspirin and clopidogrel and clinical outcomes such as stent thrombosis, major bleeding, and other adverse events.

The study enrolled 8,583 patients at 11 sites in the US and Germany who underwent a percutaneous coronary intervention (PCI) with at least one drug-eluting stent between January 7, 2008, and September 16, 2010. Researchers assessed platelet reactivity with the VerifyNow Aspirin, P2Y12, and IIb/IIIa tests. Patients were followed for one year to determine the relationship between platelet reactivity and subsequent events. At one year, stent thrombosis had occurred in 70 patients (0.8 percent), heart attack in 269 (3.1 percent), major bleeding in 531 (6.2 percent), and death in 161 (1.9 percent).

Platelet reactivity units (PRU), an index of platelet inhibition to clopidogrel, were measured by the VerifyNow P2Y12 test. High platelet reactivity, defined as a PRU of greater than 208, was present in 42.7 percent of patients. At one year, researchers found that high platelet reactivity was significantly associated with stent thrombosis (1.3 percent vs. 0.5 percent) and heart attack (3.9 percent vs. 2.7 percent), but was also found to be protective against major bleeding (5.6 percent vs. 6.7 percent). High platelet reactivity was also associated with one-year mortality (2.4 percent vs. 1.5 percent). However, because high platelet reactivity is also associated with other patient risk factors and baseline characteristics, multivariable modeling was also performed; it showed no independent association between high platelet reactivity and mortality.

"Results from the ADAPT-DES registry definitely demonstrate that high platelet reactivity after implantation of drug-eluting stents is an independent predictor of one-year stent thrombosis and heart attack, but it is also protective against major bleeding, both of which impact mortality," said lead investigator Gregg W. Stone, MD. Dr Stone is professor of medicine at Columbia University College of Physicians and Surgeons and Director of Cardiovascular Research and Education at the Center for Interventional Vascular Therapy at NewYork-Presbyterian Hospital/Columbia University Medical Center. Dr. Stone is also co-director of the Medical Research and Education Division at the Cardiovascular Research Foundation (CRF).

"Because of the counteracting effects of ischemia and bleeding, platelet reactivity was not an independent predictor of one-year mortality. Therefore, overcoming high platelet reactivity with more potent antiplatelet agents is unlikely to improve survival unless the beneficial effect of reducing stent thrombosis and heart attack can be separated from the likely increase in bleeding that results from greater platelet inhibition," said Dr. Stone.

Dr. Stone added: "Platelet reactivity on aspirin was unrelated to stent thrombosis, heart attack, or death, but may be related to bleeding. This raises questions as to the utility of aspirin in patients treated with drug-eluting stents."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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The ADAPT-DES trial was sponsored by CRF with research support from Boston Scientific, Abbott Vascular, Medtronic, Cordis, Biosensors, The Medicines Company, Daiichi Sankyo, Eli Lilly, Volcano, and Accumetrics.

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Abbott Labs And The Peripheral Stent Market

In July, Abbott Laboratories (ABT) acquired Idev, a Texas-based privately held company for $310 million. Idev makes a stent to treat blockages in leg arteries.

As demand and prices for heart stents continue to tumble, the $500 million market for peripheral artery disease market looks better every day as the next target. A blockage in the leg arteries affects about 27 million people in the U.S. and Europe, and it is fueled by rising obesity and diabetes rates.

Supera Veritas

Idev's Supera Veritas is a different class of stent. It is characterized by great flexibility and strength, a resistance to fracture and the ability to truly support the anatomy.

Veritas' design is based on biomimetic principles: attempting to mimic the body's natural movement to promote blood flow in the treated area while offering strength and flexibility. These properties are especially important in the treatment of blockages of the blood vessels in the thigh and knee where rapid and frequent movement occurs with daily activities like walking, sitting and standing.

The Veritas is a self-expanding nitinol stent built with six pairs of closed end interwoven nitinol wires with a closed cell geometry.

Supera Veritas is already approved in Europe for use in the legs. In the U.S., it is cleared for treatment of biliary strictures (narrowing of a bile duct) related to cancer. For other uses, it is still under FDA review.

In October 2012 during a VIVA (Vascular Interventional Advances) conference in Las Vegas, Kenneth Rosenfield, MD, presented findings from the Superb study.

264 subjects were enrolled in 34 sites. The mean lesion length was 8 cm, with 73 percent of the lesions having moderate to severe calcification.

Dr. Rosenfield reported that freedom from target lesion revascularization (TLR) and restenosis (a narrowing of a blood vessel), at 12 months was achieved in 79 percent of patients, easily exceeding the performance goal of 66 percent.

The primary safety endpoint was composite of all death, TLR, or any amputation of the index limb to 30 days, which was achieved in 99.6 percent of subjects, a significantly higher rate than the goal of 88 percent.

Independent core lab review of x-rays showed a stent fracture rate of 0 percent. Responses from Peripheral Artery Quality-of-Life Questionnaires showed a positive impact on the quality-of-life for patients treated with Veritas stents.

Market

The increasing prevalence of PAD is expected to place a heavy economic burden on the healthcare system. In patients with PAD, fatty deposits accumulate on the inner wall of the artery, causing blockages that reduce the flow of blood to lower parts of the leg. Patients with PAD can experience leg pain when walking and, if untreated, the disease can progress with severe consequences such as critical limb ischemia and amputation.

PAD usually affects men over age 50 and women over 65. Smoking and diabetes add to the risk. About eight million Americans have PAD, many of whom are not even aware they have the condition.

Many PAD patients aren't aware they have the disease because they may initially overlook the most common symptom, leg or foot pain while walking. In advanced stages, PAD carries a threat of amputation and even death.

Because leg arteries are subject to different physical forces than coronary arteries, some treatments derived from heart disease aren't as effective when applied to PAD.

Beyond the advice to quit smoking and eat healthy foods, there are three main treatment options for PAD patients: a drug called cilostazol (manufactured by Otsuka Pharmaceutical Co. under the trade name Pletal), the only medication specifically approved for the condition; a supervised exercise program; and procedures to clear arterial blockages, or to create a bypass around the blockages, to improve blood flow to lower legs and feet. Most patients also get drugs to lower cholesterol and blood pressure to reduce overall cardiovascular risk.

Few devices are available for treating PAD and doctors sometimes have little choice. The Wall Street Journal quotes a doctor as saying:

"Sixty to seventy percent of what we do in the vascular territory is off-label use."

The strategies for treating PAD are just emerging and their benefits remain to be proven with further study, he also said.

Zilver

With only one drug-coated peripheral stent approved in the U.S., and subsequently recalled, a bare metal device like Supera Veritas could help Abbott carve out a niche.

In April, 2013, a recall was issued for Cook Medical, Inc.'s Zilver PTX Drug-Eluting Peripheral Stent, including all sizes, diameters, and lot numbers manufactured or distributed starting December 1, 2012.

Complaints focused on the separation of the tip and inner catheter, which could impose additional surgery on patients to remove the catheter tip. Failure to do so can create thrombosis, amputation, possible cardiac arrest, and death.

In Europe, Zilver PTX has been available since September 2009. Cook is a private company and does not release sales figures, but Zilver PTX has met with success in clinical trials and uptake ought to have been good.

Cook had huge hopes for the product and the recall was a disaster.

Cook says it has altered its manufacturing process to fix the problem, but it will take time to get the FDA to sign off on the new system.

One factor in Cook's favor is the paucity of alternatives. The other possible options for treating the peripheral arterial disease include balloon angioplasty, bare-metal stents, drug therapy or surgical bypass. Medtronic (MDT) and C. R. Bard (BCR) are developing drug-coated balloons for peripheral arterial disease, but no other drug-eluting stents are likely to reach the U.S. for many years.

Balloons

An up and coming idea is the use of drug-coated balloons without stents.

Newer-generation balloons include a carrier designed to ensure that the drug remains attached to the balloon until it has been inflated and facilitates penetration into the tissue. Studies show that paclitaxel (the drug used in coating) remains in the tissue for days or weeks, even months, thereby producing a long-term effect. No hardware is left in the body.

So far, all the balloons to reach the market employ paclitaxel to guard against the vessel re-narrowing.

In coronary stents paclitaxel has been largely replaced as a coating material by the more effective 'limus mTOR inhibitors, (sirolimus, everolimus and novolimus). The reason that the mTOR inhibitors have not made a quick transition to the drug coated balloons is that, unlike paclitaxel, they are not absorbed quickly enough by the vessel wall.

Drug-coated balloons will have a good shot at the U.S. market. The leading balloon, Medtronic's IN.PACT Admiral, is slated for U.S. approval for peripheral artery disease in 2015. By that time Zilver PTX stent probably will have returned to the market, but the recall may have left a bad taste about the technology among doctors.

Competition

The delay between European and U.S. approval of medical devices is notorious and it is called the "device lag." No such lag exists in the approval of drugs.

The lag averages around three to five years. Zilver PTX, for example, saw a three-year delay, but with drug-coated balloons, it will probably be a lot more.

Analysts at Goldman Sachs say that by 2017, Medtronic and CR Bard will hold leadership positions in drug-coated balloons, with 39 percent each of the worldwide market, which will then be worth $500 million. This is a small change compared to the drug-coated stent market, which already stands at $4.5 billion and is growing.

In the peripheral arena drug-coated balloons could do well, better than in coronary artery disease where the competition is heated and the field is crowded.

Investors' summary

Analysts at Cowen point out that greater emphasis on peripheral vascular opportunities is key to Abbott's growth. The company has launched a version of Xience called Xience Prime BTK (below the knee) for critical limb ischemia in Europe, and is also pursuing CE mark for a below the knee version of the Absorb, its dissolving drug-coated stent.

Abbott's vascular products had a worldwide market share of 32 percent in 2010, according to analysts at Trefis, but this declined to around 26 percent in 2012. The company must know that the Idev acquisition alone cannot reverse this trend, though it will presumably improve it a little.

In the second quarter Abbott's total sales were $5.45 billion. Excluding currency impacts, mostly the effect of a weaker yen versus the U.S. dollar, sales grew 4.2 percent.

Abbott Labs reported a profit of $476 million and the operating margin rose to 11.5 percent from 10.6 percent.

The company's largest business is nutritional products, which includes baby formula and adult drinks marketed under the Ensure brand. Excluding currency impacts, nutrition sales rose 8.4 percent, while the company's diagnostics business reported sales growth of 7.6 percent.

Abbott's device business badly needs new directions and innovations and this must have been the thinking behind the Idev purchase. Further actions in the same direction are needed and presumably coming.

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article. (More...)

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