Year in Review: Highlights of 2010 Include Data on Valvular Therapy, CTA Progress

Interventional cardiology has explored new horizons over the past year, ranging from novel devices for treating valvular disease to expanding the frontiers of cardiac imaging. TCTMD asked several prominent interventionalists to share their views on the most significant events from 2010.

Our physician panel called out several seminal trials and trends from the past year: randomized data from the PARTNER trial on percutaneous treatment for aortic stenosis, the completion of the EVEREST II trial on mitral valve repair, the debut of a new drug to raise HDL cholesterol in the DEFINE trial, and developments in cardiac computed tomography angiography (CTA) and advanced cardiac imaging.

PARTNER

New clinical trial data presented at TCT 2010 bolstered the standing of transcatheter aortic valve implantation (TAVI) as an alternative to standard therapy in patients who are not surgical candidates.

The PARTNER (Placement of AoRTic traNscatheterER valves) trial, led by Martin B. Leon, MD,  and Craig R. Smith, MD, both of Columbia University Medical Center (New York, NY), randomized 358 patients, who had severe aortic stenosis and cardiac symptoms but were ineligible for surgery, to undergo TAVI (n = 179) or receive standard therapy (n = 179).

At 1 year, the primary endpoint of all-cause mortality showed a significant advantage for TAVI over standard therapy. The same was true for the co-primary endpoint of all-cause mortality and repeat hospitalization, as well as cardiovascular mortality and the composite of mortality and stroke. The number needed to treat in order to prevent 1 death was 5.0 (table 1).

Table 1. One-Year Outcomes

Over 1 year follow-up, the 6-minute walking distance improved in both treatment arms, but the difference was only significant for patients in the TAVI group (73 m at baseline vs. 120 m at 1 year; P = 0.002).

At 30 days, major vascular complications were higher for TAVI than for standard therapy (16.2% vs. 1.1%), as was the frequency of major bleeding episodes (16.8% vs. 3.9%; P < 0.0001 for both comparisons). The TAVI arm also showed a trend toward a higher incidence of major stroke compared with standard therapy (5.0% vs. 1.1%, P = 0.06).

EVEREST II

Earlier this year, findings presented at the 2010 American College of Cardiology Scientific Session/i2 Summit in Atlanta, GA, showed that mitral valve repair with a percutaneously delivered clip treats mitral regurgitation (MR) just as effectively as open surgery, and with lower rates of death, stroke, and other adverse events.

The MitraClip system (Abbott, Abbott Park, IL) involves a clip that is inserted into the mitral valve via percutaneous femoral venous transseptal access. The device is then passed across the mitral leaflets and used to grasp them to create a double orifice.

For the prospective EVEREST (Endovascular Valve Edge-to-edge REpair STudy) II trial, researchers led by Ted Feldman, MD, of Evanston Hospital (Evanston, IL) randomized 279 patients with significant MR (3+ to 4+) in a 2 to 1 ratio to receive treatment with the clip device (n = 184) or surgical repair/replacement (n = 95).

At 30 days, the safety endpoint of major adverse events (composite including death, major stroke, re-operation of mitral valve, MI, and several other complications) was more than 6 times lower in the device group, while the 1-year efficacy endpoint of clinical success (freedom from death, mitral valve surgery/re-operation for valve dysfunction, or MR > 2+) demonstrated noninferiority of the clip device compared with surgery (table 2).

Table 2. Primary Safety, Efficacy Endpoints

^a P for superiority.
^b P for noninferiority.

In terms of the component safety endpoints, more than half of the surgical patients (53.2%) required transfusions of more than 2 units of blood, compared with 8.8% of the device patients. Aside from 1 other patient with a GI complication requiring surgery, patients in the device group experienced no additional adverse events by 30 days. In contrast, surgery patients experienced higher rates of death (2.5%), major stroke (2.5%), mitral valve reoperation (1.3%), urgent/emergency cardiovascular surgery (5.1%), and ventilation lasting more than 48 hours (5.1%).

DEFINE

Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, can positively affect both LDL and HDL cholesterol. According to findings from the DEFINE trial, the drug showed an acceptable side-effect profile and, unlike its predecessor torcetrapib, appeared not to raise the risk of cardiovascular events.

The DEFINE trial, presented at this year’s American Heart Association Scientific Sessions 2010 in Chicago, IL, and later published online December 13, 2010, ahead of print in the New England Journal of Medicine, looked at 1,623 patients who were already taking statins and had achieved guideline-recommended LDL cholesterol levels. Subjects were randomized to receive 100 mg anacetrapib or placebo daily for 18 months.

LDL levels decreased more sharply with anacetrapib than placebo from baseline to 24 weeks, while HDL levels increased (P < 0.001 for anacetrapib vs. placebo; table 3).

Table 3. Changes in Cholesterol

Through 76-week follow-up, there were no changes in blood pressure or levels of electrolytes or aldosterone between the 2 groups. Cardiovascular events (death from cardiovascular causes, nonfatal MI, hospitalization for unstable angina, or nonfatal stroke) occurred in 2.0% of patients receiving anacetrapib and 2.6% of those receiving placebo (P = 0.40).

Commentary

Ajay J. Kirtane, MD, SM
Columbia University Medical Center
New York, NY

The presentation and publication of the PARTNER trial (see story) was a landmark event in interventional cardiology. For years, surgical aortic valve replacement has been the standard of care for the treatment of severe aortic stenosis. Unfortunately, many patients are not eligible for surgery due to advanced age and/or comorbidities, and this patient population represents a group of patients that may be ideally suited for TAVI. In a randomized, multicenter trial of patients deemed too high-risk for surgery, TAVI with the Edwards Sapien transcatheter heart valve was shown to significantly improve mortality as well as several quality-of-life measures compared with medical therapy, albeit at the expense of a modestly increased risk of periprocedural stroke.

These data are important on a number of levels. First, they offer a potential therapeutic option for previously "untreatable" patients with aortic stenosis, with improvements in both quality-of-life outcomes as well as overall mortality. Second, they demonstrate the feasibility and effectiveness of an early generation TAVI device, heralding a potential revolution in the minimally invasive treatment of structural heart disease. With the publication of PARTNER, there has clearly been a sea change in interventional cardiology. This broadening of the field addresses diseases that had previously been within the realm of cardiothoracic surgery.

Ted Feldman, MD
Evanston Hospital
Evanston, IL

Completion of the EVEREST II randomized trial (see story) comparing percutaneous mitral valve leaflet repair using the MitraClip device with surgical mitral valve repair or replacement represents a landmark not only for the year, but also more broadly for valve therapy.

MitraClip is the first percutaneous mitral valve device to complete a randomized trial. EVEREST II is the first prospective multicenter trial comparing transcatheter and surgical mitral valve repair to have an independent core lab and clinical events committee adjudication. The trial overall demonstrated superior safety for percutaneous mitral repair compared to surgery, with lesser efficacy for reduction in mitral regurgitation. Both percutaneous and surgical approaches showed important reductions in left ventricular chamber dimensions after 1 year and improvements in quality of life. Among the various approaches to percutaneous therapy for mitral repair, coronary sinus annuloplasty was the one predicted several years ago to complete its evaluation phase first, due to the technique’s ease of use. Now the technique of leaflet repair has significantly outdistanced the various other percutaneous treatments and is now undergoing rapid adoption in Europe, where it has been approved since 2008. The presentation of EVEREST II trial results in the United States will begin the process to further advance this therapy here.

Bernard J. Gersh, MB, ChB, DPhil
Mayo Clinic
Rochester, MN

Will the DEFINE trial be looked upon in the future as a defining moment in cardiology? We will undoubtedly know in time, but for now this trial points us in new clinical directions.

There is abundant epidemiologic evidence to show that elevated LDL and reduced HDL cholesterol levels are major risk factors for the development of cardiovascular disease. Despite the remarkable success of statins in reducing LDL cholesterol and cardiovascular events—both in patients with and without CAD—it should be appreciated that a high residual risk of cardiovascular events persists even while on statin therapy and particularly in the presence of other lipid abnormalities such as low HDL cholesterol (LaRosa JC. N Engl J Med. 2005;352:1425-1435).

One approach to raising HDL cholesterol is to inhibit CETP, as this protein promotes the transfer of cholesteryl esters from HDL and other lipoprotein fractions. A previous trial with a CETP inhibitor, torcetrapib, was terminated due to an excess of deaths and cardiovascular events. These were subsequently thought to have arisen from drug-induced increases in aldosterone levels and blood pressure (Barter PJ. N Engl J Med. 2007;357:2109-2122). These adverse effects, however, are believed to be unrelated to CETP inhibition and as such are not necessarily shared by other members of the class of CETP inhibitors.

The DEFINE trial demonstrated quite emphatically a striking effect of anacetrapib on reducing LDL cholesterol and increasing HDL cholesterol (in patients already on statins) but without changes in blood pressure, aldosterone, or electrolyte levels.

This moderately sized safety study demonstrated efficacy in regard to lipid levels, but this benefit does not necessarily translate into a reduction in clinical events. A legitimate question is whether the HDL particles generated by CETP inhibition are as protective functionally as naturally occurring HDL, which does appear to be atheroprotective. Preliminary in vitro studies in this respect are, however, encouraging (Yvan-Charvet L. Arterioscler Thromb Vasc Biol. 2010;30:1430-1438). In this regard, it is interesting that DEFINE observed no effect on CRP levels with anacetrapib. The finding may or may not bear on whether the drug will be successful in reducing clinical events in the future.

Whether elevating HDL cholesterol with CETP inhibitors would lead to a reduction in cardiovascular events awaits the results of large phase III studies. If these are positive, this will certainly usher in a new era in preventive cardiology, and it goes without saying that the results of these trials are eagerly awaited. Moreover, several other strategies aimed at raising HDL cholesterol are under investigation, and hopefully we may in the future be able to take advantage of HDL’s protective benefits using pharmacologic and genetic approaches (Shah PK. Curr Opin Cardiol. 2010;25:603-608).

Robert S. Schwartz, MD
Minneapolis Heart Institute
Minneapolis, MN

This year, there were several developments in cardiac computed tomographic angiography (CTA) and advanced cardiac imaging. Cardiac CTA continues to move forward at an accelerating pace. Novel developments are poised to revolutionize both our noninvasive and invasive understanding of the cardiovascular system, including the heart, coronary arteries, and peripheral vasculature. CTA is also transforming clinical practice by helping physicians better understand and plan interventional approaches to chronic total occlusion and TAVI.

High quality CT images are now possible at radiation doses as low as 0.5 mSv using novel scanning protocols and dual-source X-ray sources. This compares with 0.1 mSv for a chest X-ray and 10 to 12 mSv for a nuclear perfusion scan. Other studies including those requiring ventricular function are also possible at doses of 5 mSv or less.

Pediatric cardiologists in particular are beginning to take advantage of X-ray dose reduction. Very rapid scans (less than 1 second) enable highly accurate, highly diagnostic, and markedly improved methods for pediatric diagnosis. This technique eliminates the need for general anesthesia, allowing patients to undergo mild sedation instead. This also enables true 3-D capability for improved diagnosis.

Applications for CTA

New software has made it possible not only to visualize coronary artery anatomy and plaque but also to image and quantify myocardial perfusion. Multiple trials are now underway to establish the ability of this technology to simultaneously look at structure and function. If these studies are successful, a single sub-second scan will identify stenoses and assess their location, severity, and impact on flow.

CTA can now also measure the volume of all 4 cardiac chambers over time and in 3 dimensions. The method is highly accurate and automated, and the data are available for both the left and right sides of the heart. This technique promises to allow rapid, quantitative diagnosis of pathology such as systolic and diastolic dysfunction, heart failure, and valvular heart disease.

Thanks to novel software, fractional flow reserve (FFR) can now be assessed noninvasively. This technology uses sophisticated computational fluid dynamics and immense computer power to rapidly and accurately calculate FFR for any and all lesions of the coronary arteries, as shown in pilot studies. A multicenter clinical trial aimed at invasive validation of the technology has begun in the United States. If successful, FFR has the potential to offer monumental clinical benefits.

3-D Analysis and Plaque Characterization

Hollywood had committed major resources toward producing true 3-D imaging for entertainment. Technology that can show 3-D images, including flat-panel displays and specialized glasses, is now readily available to consumers at reasonable cost. Early application of these technologies to cardiac and vascular imaging has been remarkable and suggests they will be an exciting addition to diagnostic and procedure planning. Film directors such as James Cameron and Stephen Spielberg have expressed early interest in promoting these technologies for medical benefit.

Improvements in imaging technology may also increase understanding of plaque vulnerability. Intravascular ultrasound showed promise in the PROSPECT trial, and CTA is being used to identify lesions that might lead to acute coronary syndromes. Highly remodeled lesions consisting of mixed calcific and noncalcific components as well as more severe stenoses are emerging as culprit ACS lesions. These features are readily identified by CTA, and invasive assessment with IVUS and optical coherence tomography will help determine their clinical impact.

 

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Sources:
1. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363:1597-1607.

2. Feldman T. Endovascular Valve Edge-to-edge REpair Study (EVEREST II). Presented at: American College of Cardiology Annual Scientific Session/i2 Summit; March 14, 2010; Atlanta, GA.

3. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapid in patients with or at high risk for coronary artery disease. N Engl J Med. 2010;Epub ahead of print.

 

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