CD&D Contributing Editor

ORLANDO, Florida – The interventional cardiology device market, historically one of the most dynamic segments of the worldwide medical device market, has, like many markets in today's economy, experienced a significant slowdown. The overall market trend, however, masks some dramatic changes within the sector, including shifts in market share for certain competitors, and also the emergence of new segments of the market that represent attractive growth opportunities.

Many of the new developments in interventional cardiology were highlighted at ACC.09 & I2 Summit, the recent annual meeting of the American College of Cardiology (ACC, Washington). Devices for treatment of structural heart defects, including congenital defects such as patent foramen ovale (PFO) as well as valvular disease, were spotlighted at the conference, along with advances in drug-eluting stents, adjunctive pharmacological therapies, and devices for treatment of stroke.

Heart failure therapy was an important focus at the ACC sessions, including new heart assist devices and device-based technologies for treatment of hypertension. Advances in diagnosis and monitoring of patients with heart disease were also described that promise to greatly improve the ability of physicians to diagnose myocardial infarction as well as to manage patients with arrhythmias and heart failure.

Dramatic shifts in DES market

The pace of development in the drug-eluting stent sector remains strong, although no major new advances were reported at the ACC conference. Dramatic shifts in market share have occurred over the past year, however, demonstrating the continued volatility within the segment which has declined substantially in value since reaching $5.4 billion worldwide in 2006. The market's decline has resulted both from a drop in DES procedures as well as from a decline in price, from $2,330 in 2006 to between $1,900 and $2,000 now.

Abbott Vascular (Santa Clara, California) has captured a dominant market share position in the U.S. (Table 1), and also is the leader in the DES market internationally according to the company, since launching the Xience V stent in the U.S. market in July 2008. One year ago, in March 2008, data from Abbott showed that the Boston Scientific Taxus held a U.S. share of about 45%, followed by Cordis with a 40% share and Medtronic with a share of about 15%.

The current share for Abbott's Xience platform, which also is used for the Promus under an agreement between Abbott and Boston Scientific, is even higher, in excess of 50% in the U.S. The introduction of second-generation DES such as Xience V has helped to revive growth in the drug-eluting stent market, according to Gregg Stone, MD, who discussed the most recent results of DES clinical trials at an Abbott-sponsored satellite conference held in conjunction with the ACC meeting. According to Stone, DES utilization in the U.S. has increased from 61% of coronary stent implants in November 2007, shortly after reports surfaced in Europe of adverse events involving late thrombosis, to 76% in January 2009.

Issues with first-generation drug-eluting stents included not only a 0.4% continuing mortality rate due to late stent thrombosis, but also a high rate of stent fractures particularly for stents implanted in saphenous vein grafts and chronic total occlusions, reaching a rate of 15%-20% in total occlusions and associated with restenosis and aneurysm formation. Second-generation DES such as Xience V and Endeavor are fabricated of cobalt-chromium, a softer, more malleable metal; have 50% thinner struts; and employ a different polymer compared to the ones used in first-generation devices which were associated with inflammation of the vessel wall.

Optimization of second-generation designs has enabled more rapid endothelialization of the stent, quoted at 14 days by Stone for Xience, and lower rates of late thrombosis, stimulating utilization. Stone predicted that DES utilization will increase to 80% nationwide, similar to the 85% rate in his practice.

Results of the SPIRIT III trial of Xience V presented by Stone show a significant improvement in major adverse cardiovascular events of 6.4% for Xience vs. 14.9% for TAXUS, driven primarily by a considerably lower mortality rate of 0.5% compared to 4.2%. Stent thrombosis for Xience is 0.9% at three years versus 2.8% for Taxus a three-fold reduction, while the target lesion revascularization rate is halved to 4.2% versus 9.4% for Taxus at three years.

Stone said he expects definitive results from the SPIRIT IV trial, a 3,690-patient randomized controlled trial comparing Xience V to Taxus, to be presented in September. However, the market share data demonstrate that cardiologists have not waited for the results of long-term trials before deciding to switch to second-generation devices. In addition to the improved results with respect to safety and efficacy, second-generation stents such as Xience V also are much more deliverable, further enhancing their utilization.

In addition to the competition between devices within the DES market, there also is competition for drug-eluting stents from alternative therapies, principally coronary artery bypass graft (CABG) surgery and to a lesser extent with medical therapy. The latest results from the Synergy between PCI with Taxus And Cardiac Surgery (SYNTAX) trial, presented at the ACC conference by David Cohen, MD, of Saint Luke's Mid America Heart Institute (Kansas City, Missouri), show that drug-eluting stents, as exemplified by Taxus, are a better option for patients with noncomplex or intermediate coronary artery disease when clinical outcome, cost and quality of life are considered, whereas for patients with the most severe disease, CABG is the best option.

As in many other studies of PCI vs. CABG, the SYNTAX trial showed that the primary difference in outcome is the number of repeat procedures performed, at least at one-year follow-up. However, costs for the first year are less for stents, and quality of life was rated higher for patients with uncomplicated and intermediate disease treated with stents. The results would presumably favor stents for less severe disease even more if second-generation stents, which exhibit lower rates of re-intervention versus Taxus, were compared to CABG.

In addition, the cost equation is expected to change soon in favor of stents when a generic version of clopidogrel (Plavix, a drug from Sanofi-Aventis) becomes available, since about $1,000 of the additional $2,500 in one-year follow-up costs for stenting is due to the cost of Plavix therapy.

Cohen said that an important new finding from the SYNTAX trial is that quality of life and cost are important factors in selecting treatment modalities, which in the case of PCI in less severe disease outweigh the benefit of fewer repeat procedures with CABG.

New drug-eluting stents now under development could show further benefits in terms of reduced restenosis and lower event rates. A new stent being developed by Elixir Medical (Sunnyvale, California), described at the ACC conference by Alexandre Abizaid, MD, of Dante Pazzanese & Albert Einstein Hospital (Sao Paulo, Brazil), employs a cobalt-chromium platform and either durable or bioabsorbable polymers eluting Novolimus. Initial studies with the Elixir stent show a late loss of 0.15 mm at four months, and only 6% stent obstruction of the vessel at six months.

Elixir, which first will introduce a bare-metal coronary stent, also is developing fully bioabsorbable stents. Bioabsorbable stents represent a third generation of coronary stent technology.

Most attempts to develop fully bioabsorbable stents have been unsuccessful, including the Igaki-Tamai stent, a PLLA-based device for which development was recently terminated. One of the newest bioabsorbable stent designs, however, the BVS from Abbott Vascular, has performed well in trials, and may usher in yet another wave of technological competition in the drug-eluting stent market. The Abbott BVS is a polylactic acid stent loaded with everolimus, the same drug used in Xience V.

As discussed by Patrick Serruys, MD, PhD, of the Thoraxcenter at Erasmus University (Rotterdam, the Netherlands), at the ACC sessions, two-year data from the 30-patient ABSORB trial of the BVS demonstrated complete absorption of the stent, no target lesion revascularization, a low 3.6% MACE rate, and no deaths, with all patients no longer receiving adjunction clopidogrel therapy. An increase in minimum lumenal diameter is observed over time, along with a decrease in plaque area.

Notably, there was some evidence of incomplete apposition of the stent struts at six month follow-up, with the vessel wall apparently receding away from the stent structure, but by two years the struts were completely absorbed. An important finding, which could differentiate absorbable stents from current stent designs, is an increase in vasomotion of the stented region at two years. That feature could enable the treated vessel to revert to a normal state, vs. the constrained configuration that results with a permanent implant.

A promising study using drug-eluting stents to prevent stenosis in saphenous vein grafts was described at the ACC sessions by Josep Rodes-Cabau, MD, of Quebec Heart Institute. The Vein Graft Lesion Stenting with the Taxus Stent and Intravascular Ultrasound (VELETI) trial is the first trial to assess the use of stenting to prevent blood vessel narrowing rather than to treat stenosis after it develops.

Saphenous vein grafts used in coronary artery bypass have a high failure rate, quoted at up to 50% at 10 years by Rodes-Cabau, and can develop stenosis in spite of optimal control of risk factors such as LDL cholesterol levels. In fact, in the patients studied in the VELETI trial, 22% of patients treated with medical therapy alone who had mean LDL levels of less than 80 mg/dL developed a severe lesion or graft occlusion at 12 months, whereas patients who received drug-eluting Taxus stents to prevent progression of stenosis in moderate, non-significant lesions had no severe lesions or occlusions.

From 1994 through 2004, a total of 3.54 million patients had a CABG procedure in the U.S., each receiving about three grafts per procedure. There thus is a large potential patient population that could benefit from preventative stent therapy for saphenous vein graft disease. New technologies are also now available that could help to identify target sites in the coronary vessels which could benefit from preventative stent treatment.

InfraReDx (Burlington, Massachusetts) exhibited its LipiScan coronary imaging system at the ACC sessions, which was first introduced in April 2008. The LipiScan employs near-infrared imaging to detect vulnerable coronary plaques with a lipid-rich core and a thin fibrous cap. The system can potentially be used to identify plaques which are most likely to rupture, helping to target focal treatment such as DES implantation.

The LipiScan includes an image analysis algorithm designed to detect thin cap fibrous atheromas, and although an optical imaging technology, does not require occlusion of blood flow in order to acquire an image. The system is priced at $150,000, with single-use catheters priced at $2,400. So far, InfraReDx has placed the LipiScan in 10 sites in the U.S., and is pursuing regulatory clearance in Canada and Europe to further expand sales.

Optimization of adjunctive anti-coagulation drug therapy for DES patients is a topic of ongoing investigation. At present, recommendations from the FDA and the ACC are for maintenance of dual anti-platelet therapy with aspirin and clopidogrel for at least one year to prevent stent thrombosis, and some cardiologists recommend continuation of therapy indefinitely in the absence of side effects or a change in risk factors for bleeding. However, as discussed by Paul Gurbel, MD, of the University of Maryland, Baltimore at the ACC sessions, there is significant variability in patient response to dual anti-platelet therapy. In fact, more than 20% of patients are poor responders to therapy, and are consequently not protected from potentially life-threatening blood clots.

In patients with DES implants, between 23% and one-half of all late stent thrombosis events occur in patients who are taking dual anti-platelet therapy, according to data published by Chris Terpening, PhD, in the January edition of The Journal of the American Board of Family Medicine, again indicating that a significant proportion of patients do not respond to therapy. Gurbel has assessed the use of genetic testing combined with point-of-care anti-platelet drug response testing to develop a personalized medicine approach to delivering anti-platelet therapy.

The study employed a genetic assay developed by the Applied Biosystems unit of Life Technologies (Carlsbad, California) which detects the CYP2C19*2 variant related to clopidogrel resistance, along with a turbidimetric platelet function assay. The CYP2C19*2 gene variant occurs in 30% of the U.S. population. Gurbel's study showed a significantly higher rate of thrombosis events in carriers of the gene variant compared to non-carriers.

A similar study presented by Jean-Philippe Collet, MD, of the Institut de Cardiologie at Hopital la Piti Salp tri re (Paris) which evaluated young DES patients undergoing dual anti-platelet therapy using the VerifyNow platelet function testing system from Accumetrics (San Diego) along with genetic testing, found that seven of 33 were non-responders to clopidogrel, even at two times the normal dose, and six of the seven were carriers of the CYP2C19*2 variant. Increasing the dose to three or four times normal did not completely eliminate resistance, and some patients were unable to tolerate a higher dose. The patients all had experienced an initial stent thrombosis as well as a recurrent thrombosis.

When the clopidogrel-resistant patients were switched to prasugrel, a new anti-platelet drug from Eli Lilly (Indianapolis, Indiana) and Daiichi Sankyo (Tokyo), all responded. Collet is now conducting the Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation, and Interruption Versus Continuation of Double Antiplatelet Therapy (ARCTIC) trial in Paris using the VerifyNow point-of-care assay along with genetic testing to guide anti-platelet therapy.

He recommends that non-responders to clopidogrel be switched to prasugrel, now available in Europe as Efient and pending FDA approval in the U.S., while those who respond to clopidogrel remain on that drug due to the higher bleeding risk associated with prasugrel.

The use of clopidogrel, marketed as Plavix by Sanofi-Aventis (Paris) and Bristol-Myers Squibb (New York), for prevention of thrombosis in DES patients has helped to make that drug the No. 2 best-selling pharmaceutical worldwide, with about $7 billion in sales, 28 million users, and over 6.5 million new prescriptions written annually to prevent stent occlusions as well as heart attacks, stroke, and other types of blood clots. Plavix costs about $4 per tablet in the U.S., but the price is expected to drop when the product becomes generic in 2011.

A new application for clopidogrel, described at the ACC conference by Stuart Connolly, MD, of McMaster University (Hamilton, Ontario), could expand the market for the drug. Connolly presented results from the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events - Aspirin (ACTIVE-A) trial, which compared the use of clopidogrel plus aspirin to aspirin alone for prevention of stroke and heart attack in 7,554 patients with atrial fibrillation, making it the largest trial of anti-thrombosis drug therapy in atrial fibrillation patients.

The results for a 75 mg daily dose showed that 28 strokes and six heart attacks were prevented per 1,000 patients treated, with an increase in major hemorrhages of 20 per 1,000 patients. The study was designed to evaluate clopidogrel as an alternative for stroke prevention in AF patients who are unable to take warfarin. There are 7 million patients worldwide with atrial fibrillation, according to Connally, and four million patients taking warfarin in the U.S.

About 20% of all strokes are due to atrial fibrillation, and half of those strokes are fatal or result in severe neurological complications. Stroke risk in the atrial fibrillation population is elevated by six-fold.

The growing number of patients taking clopidogrel is likely drive an expansion of the market for products used to guide therapy such as the VerifyNow and perhaps for genetic testing products. In addition, the sector is attracting new competitors. For example, Thrombovision (Houston) exhibited its development-stage T-Guide system, a low-cost point-of-care system for measuring aspirin and Plavix resistance. The T-Guide is undergoing 510(k) review by the FDA following a filing by the company in July 2008.

The system will be targeted at use in the physician's office, catheterization labs, and surgery centers, and will provide results in five minutes using a 2.7 ml blood sample. Marketing clearance is expected sometime in Q2 2009.

Four genotyping systems have been cleared for marketing by the FDA for genotyping to determine warfarin sensitivity, including the EQ-PRC Warfarin Genotyping Kit from Trimgen (Sparks, Maryland), the E-Sensor Warfarin Sensitivity assay from Osmetech (Pasadena, California), the Infiniti 2C9 and VKORC1 tests from Autogenomics (Carlsbad, California), and the Verigene Warfarin Metabolism test from Nanosphere (Northbrook, Illinois).

Devices for structural heart disease

In addition to advances in drug therapies to prevent stroke in patients with atrial fibrillation, advances were described at the ACC conference in device-based therapies for stroke prevention as well as for treatment of heart valve disorders. As reported in Cardiovascular Devices & Drugs' coverage of last year's ACC conference, a new device for stroke prevention, the Watchman, is under development by Atritech (Plymouth, Minnesota), and is undergoing a pivotal clinical trial, the PROTECT AF trial. Some 800 patients have now been randomized, comparing the Watchman to warfarin therapy, according to David Holmes, MD, of the Mayo Clinic (Rochester, Minnesota), with a mean follow-up of five years.

The device is used for closure of the Left Atrial Appendage (LAA), which is believed to play a significant role in increasing the risk of stroke in patients with atrial fibrillation. Some 80% of patients with atrial fibrillation are under-treated with conventional warfarin therapy due to drug intolerance, resistance, or lack of compliance, leaving them at elevated risk of stroke. Between 91% and 98% of the thrombi found in atrial fibrillation patients occur in the LAA, making it a prime target for stroke prevention therapies.

The Watchman device consists of a nitinol frame with a poly ethylene terephthalate cap containing small orifices that become occluded by cell ingrowth. The device is placed into the orifice of the LAA and released, resulting in sealing of the channels within the LAA and elimination of the risk of clot formation.

As reported by Holmes, the latest data including outcomes for 707 patients, 463 in the device group and 244 in the warfarin group, show that the device is equivalent to warfarin therapy for prevention of occlusive stroke, and superior for hemorrhagic stroke prevention. The Watchman is particularly beneficial for high-risk patients, according to Holmes. In the group treated with warfarin, there were six hemorrhagic strokes versus one in the device group. There were 11 strokes of all types in the warfarin group versus 12 in the device group, corresponding to a 30% reduction in the combined risk of cardiovascular death and stroke for device therapy.

A number of procedure-related complications, primarily pericardial effusions, were noted in the early phase of the trial, but the complication rate dropped from 4.4% to 1.1% as the trial progressed due to improved training of the operators. The Watchman has been approved in Europe with a CE mark since 2005, but the company has not commenced sales.

Atritech expects an FDA panel review in April. The target patient population is essentially all patients with nonvalvular atrial fibrillation. Cost of the device is not yet determined, but will probably be similar to the cost of PFO closure devices (about $5,000), resulting in a very large potential market.

Another emerging segment of the interventional device market, minimally invasive heart valve repair and replacement devices, was also highlighted at the ACC conference. As shown in Table 2, numerous devices are under development and four have now received a CE mark allowing sales to begin in Europe.

Edwards Lifesciences (Irvine, California) reported net sales in Europe of $50.1 million in 2008 for the Sapien transcatheter heart valve, following launch of the product in 4Q07, well above the level forecast in mid-2008 of $20 million.

Although one company in the segment, Myocor (Maple Grove, Minnesota), recently folded, and development of another, the AorTx valve, has been halted, development activity is intense and the number of implants worldwide is growing rapidly.

As discussed by Martin Leon, MD, of Columbia University Medical Center (New York), at the ACC conference, more than 200 centers worldwide are now implanting transcatheter heart valves, and it is estimated that in excess of 16,000 will have been implanted by the end of 2009. While conventional surgically implanted valves show good efficacy and outcomes, a large number of patients are not referred for therapy. Leon said that 31.8% of patients identified in the 2004 Euro Heart Survey as having aortic stenosis were not treated surgically, and estimated that almost 250,000 patients in the U.S. with severe aortic stenosis likewise go untreated.

Reasons for lack of treatment include advanced age (over 80); co-morbidities such as COPD, cirrhosis, porcelain aorta, neurocognitive dysfunction; and frailty, all of which put patients at high risk for adverse events if surgery is performed. Many of those patients are candidates for treatment with minimally invasive techniques.

Another indicator of the growing importance of the market for transcatheter valves is the recent purchase by Medtronic of both CoreValve and Ventor, for a combined price of $1.03 billion. Recent advances include CoreValve's introduction of an 18 Fr delivery system, making the procedure a true cath lab operation according to Leon; introduction of the Edwards Sapien XT valve with a new frame material providing a 15-year estimated life; and improved procedural success rates reaching 98% as devices are improved and physician experience grows. Durability of transcatheter valves appears good, with no valve failures reported at up to five years post-implant.

Progress in transcatheter valves for mitral repair has been less rapid, with less than 1,000 implanted so far, of which about 75% are Evalve devices. There are about 250,000 new diagnoses of mitral insufficiency each year, but only 50,000 or 20% undergo surgery due to increased surgical risk. Outcomes so far for patients treated with transcatheter mitral valve implants are good, however, with 96% of patients surviving at three years, 82% free from surgery, and 63% having no significant mitral regurgitation (no MR>2+). Mortality is equivalent to that for open surgical repair, and many patients show progressive improvement in symptoms, with the rate of hospitalizations in heart failure patients with MR dropping by half.

Factors limiting expansion of the transcatheter valve market, according to Leon, include the need for hybrid ORs combining surgical and cath lab facilities as well as the need to form surgeon/cardiologist teams to perform procedures most effectively, with attendant issues related to reimbursement. There is also a relatively high incidence of perivalvular leaks with existing transcatheter valves, which needs to be resolved to optimize outcomes. Training also is challenging, such that transcatheter valve procedures are not likely to be performed by all interventional cardiologists.

Leon predicts that, as devices continue to be reduced in size, all procedures will eventually be performed percutaneously, with the transapical approach, which is now used in about 50% of cases performed in Europe with the Edwards valve, eventually disappearing.

Devices for hypertension and stroke

A significant advance in the treatment of drug-resistant hypertension was announced at the ACC conference by Marcos Rothstein, MD, of Washington University School of Medicine (St. Louis). Rothstein described results of studies with the Rheos System, an implantable neurostimulation device under development by CVRx (Minneapolis). As shown in Table 3, between 1 million and 3.5 million patients in the U.S. and at least twice that number worldwide are potential candidates for device-based hypertension therapy.

The Rheos System consists of an implantable pulse generator and implantable baroflex sensors placed in the carotid arteries. The system applies a voltage to the biological sensors in the carotids which regulate blood pressure, producing drops in both heart rate and blood pressure. The stimulus can produce drops in blood pressure of more than 60 mm in both systolic and diastolic pressure, from 210/96 to 144/66 for example, as well as a decline in heart rate from 71 to 50 beats per minute.

In pilot studies conducted in the U.S. and Europe involving 38 patients, a 31% decline in systolic pressure was achieved at three years, along with a 21% drop in diastolic pressure and a 5 bpm drop in heart rate. Patients have been able to reduce their use of anti-hypertensive medications, and severe abnormalities in hypertension have been diminished. Rheos therapy also has been shown to provide benefits in cardiac structure and function.

The system is now being evaluated in a 300-patient Phase II trial in the U.S., with a prescribed goal of reducing mean pressures by 10 mm or more. The blood pressure reductions observed in clinical studies to date, which have averaged about 30 mm, are significantly higher than would be expected from medical therapy, according to Rothstein, making the Rheos system attractive for treatment of drug-resistant patients.

So far, 230 patients have received Rheos implants in clinical trials worldwide, including 160 in the U.S. Implantation of the simulation leads is performed under general anesthesia in a procedure that is similar to a carotid endarterectomy, while the generator is implanted much like an ICD. Cost is estimated to be between that for a pacemaker and an ICD. CVRx estimates that, in the best case, market launch will not occur until 4Q11 or 1Q12.

Device-based treatments for stroke also are progressing. Devices for stroke treatment include the Merci Retriever from Concentric Medical (Mountain View, California), the Export XT aspiration catheter from Medtronic, the Penumbra System from Penumbra (Alameda, California), and the Flow Reversal System from W.L. Gore (Flagstaff, Arizona), as well as development-stage thrombectomy catheters from NeuroInterventions (Pittsburgh).

In addition, as discussed by Nelson Hopkins, MD, of State University of New York at Buffalo, at the ACC sessions, the WingSpan stent from Boston Scientific (Natick, Massachusetts) is proving to be a valuable device in some stroke patients, along with the Enterprise stent from Cordis/J&J (Miami Lakes, Florida).

For patients with ischemic stroke, recanalization of the occluded vessel is typically an important treatment objective, although so far the benefit of using a device to re-open a blocked artery in stroke patients has not been demonstrated in randomized trials with respect to hard endpoints such as mortality. There is some controversy regarding the FDA's market clearance for the MERCI device, since it was not based on randomized trial data but rather on demonstration of substantial equivalence to approved devices such as endovascular snares.

In addition, reimbursement for use of the Merci device through Medicare is substantially higher than for thrombolytic therapy using tPA, complicating efforts to conduct an adequately powered randomized trial. About 10,000 MERCI devices have been sold since market clearance was received in 2004.

Nevertheless, according to Hopkins, devices such as the Merci Retriever and other mechanical approaches using guidewires or snares to remove clots are successful in only 60% to 70% of cases where they are used. For the remaining 30%, stenting has been employed experimentally, typically as a last resort, initially using existing coronary stents such as the Abbott Vision. Hopkins has now begun using the WingSpan stent as well as the Cordis Enterprise in patients who cannot be recanalized by other techniques with considerable success.

In the Stent-Assisted Revascularization for Ischemic Stroke (SARIS) study using the WingSpan, which included patients with an average NIH Stroke Scale score of 14, 100% revascularization was achieved, and the mean time from puncture to recanalization was only 24 minutes. The mortality rate at one month was 25%, similar to that for other stroke trials according to Hopkins.

The WingSpan has been approved by the FDA under the Humanitarian Device Exemption (HDE) program. As opposed to coronary stents used experimentally in the cerebral vessels, Hopkins has not found access through the tortuous vessels at the base of the skull to be an issue with the WingSpan.

Hopkins is now also using the Cordis Enterprise, a closed cell nitinol stent which can be partially deployed and then removed if the vessel remains open with stable flow. Otherwise, the stent is fully deployed to keep the vessel open. The Enterprise, like the WingSpan, was FDA approved under a HDE, although the intended use is for vascular reconstruction in the cerebral vessels for treatment of aneurysms.

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