From the approval of a device to prevent stroke in patients with atrial fibrillation (A-fib) to a new antiplatelet agent topping standard thienopyridine therapy in head-to-head trials, the past year has seen important developments in the field of interventional cardiology. TCTMD asked several prominent interventionalists to share their views on the most significant events from 2009.
Our physician panel called out several seminal trials and events from the past year: Approval of the Watchman device based on PROTECT-AF, as well as the PLATO, BARI 2D, EVEREST, and PROSPECT trials.
Watchman
A percutaneously implanted left atrial appendage occlusion device won the recommendation of a US Food and Drug Administration advisory panel on April 23, 2009, for its ability to protect against stroke in patients with nonvalvular A-fib.
The Circulatory System Devices Panel voted 7 to 5 in favor of the Watchman device (Atritech, Plymouth, MN), a fabric-covered nitinol cage developed to prevent embolization of thrombi that form in the left atrial appendage (LAA).
The narrow victory came with several stipulations, among them the unexpected decision that the device should be approved in warfarin-eligible patients only. The caveat appears to stem from the design of the device’s pivotal premarket approval study, PROTECT-AF. In order to be eligible for the trial, patients had to have been able to take warfarin and also able to stop taking warfarin after 45 days if randomized to the device group.
Results from PROTECT-AF, published in the Lancet in August 2009, showed that closing off the LAA with the Watchman device may allow A-fib patients to forgo long-term warfarin therapy.
For the multicenter noninferiority trial, researchers led by David R. Holmes, MD, of the Mayo Clinic (Rochester, MN), randomized 707 patients with nonvalvular A-fib in a 2:1 ratio to percutaneous closure of the LAA using the Watchman device with the aim of discontinuing warfarin after 45 days (n = 463) or ongoing warfarin treatment alone (n = 244).
Comparable Efficacy, Poorer Safety
The Watchman device was successfully implanted in 88% of patients randomized to the treatment arm. Based on an intent-to-treat analysis, after 1,065 patient-years of follow-up, rates of the primary efficacy endpoint (composite of stroke, cardiovascular or unexplained death, and systemic embolism), as well as all-cause mortality and stroke, were lower in the intervention group compared with the control group. However, primary safety events (major bleeding and procedure-related complications) occurred more frequently in the intervention group (table 1).
Table 1. Outcomes for Watchman vs. Warfarin
Events/100 Patient-Years
|
Watchman
(n = 463)
|
Warfarin
(n = 244)
|
Primary Efficacy Endpointa
|
3.0
|
4.9
|
All Stroke
|
2.3
|
3.2
|
All-Cause Mortality
|
3.0
|
4.8
|
Primary Safety Endpointb
|
7.4
|
4.4
|
a Composite of stroke, cardiovascular death, and systemic embolism.
b Major bleeding or serious procedure-related complications.
PLATO
In 2 separate studies, the new antiplatelet agent ticagrelor showed strong reductions in hard clinical endpoints compared with clopidogrel.
Researchers led by Philippe Gabriel Steg, MD, of Hôpital Bichat-Claude Bernard (Paris, France), randomized 8,430 STEMI patients undergoing primary PCI to a 180-mg dose of ticagrelor followed by 90 mg daily (n = 4,201) or to a 300-mg dose of clopidogrel followed by 75 mg daily (n = 4,229) for 6 to 12 months.
The investigators found significant reductions in the primary endpoint (CV death, MI, or stroke), as well as in all-cause death and ARC-defined definite stent thrombosis at 1 year (table 2).
Table 2. One-Year Outcomes
|
Ticagrelor
|
Clopidogrel
|
P Value
|
CV Death, MI, or Stroke
|
9.3%
|
11.0%
|
0.02
|
All-Cause Death
|
4.9%
|
6.0%
|
0.04
|
Definite ST
|
1.6%
|
2.5%
|
0.01
|
In another study, researchers led by Christopher P. Cannon, MD, of Brigham and Women’s Hospital (Boston, MA), randomized 13,408 patients with ACS indicated for interventional therapy to ticagrelor (n = 6,732) or clopidogrel (n = 6,676) for 6 to 12 months. The primary endpoint was CV death, MI, or stroke.
The investigators found a 16% reduction in the primary endpoint at 1 year with ticagrelor vs. clopidogrel. There was also a 19% decrease in all-cause mortality as well as reductions in CV death and MI with ticagrelor (table 3).
Table 3. One-Year Outcomes
|
Ticagrelor
|
Clopidogrel
|
P Value
|
CV Death, MI, or Stroke
|
9.02%
|
10.65%
|
0.0025
|
CV Death
|
3.4%
|
4.3%
|
0.025
|
MI
|
5.3%
|
6.6%
|
0.002
|
BARI 2D
The BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial enrolled 2,368 patients with type 2 diabetes and angiographically documented stable CAD. After angiography but prior to randomization, patients were assigned by their physician to a strategy of CABG (n = 763) or PCI (n = 1,605). Within these subgroups, patients were then randomized to: (1) medical therapy with or without early revascularization and (2) insulin-sensitization drug therapy or insulin-provision drug therapy.
The main results from the trial, published June 11, 2009, in the New England Journal of Medicine, showed that 5-year rates of survival and freedom from MACE were similar for early revascularization vs. medical therapy alone and insulin sensitization vs. insulin provision. However, in the CABG subgroup, the MACE rate was significantly lower with revascularization (22.4%) than with medical therapy (30.5%; P = 0.01). The positive impact of early revascularization in the CABG subgroup was particularly evident in patients assigned to the insulin-sensitizing strategy, imparting a MACE rate of 18.7% vs. 32.0% with medical therapy (P = 0.002). No such advantage from revascularization was seen in the PCI subgroup.
EVEREST
For the EVEREST (Endovascular Valve Edge-to-Edge REpair Study) trial, researchers led by Ted Feldman, MD, of Evanston Hospital (Evanston, IL), assessed 107 candidates for mitral valve repair or replacement surgery who were selected to receive the MitraClip device (Evalve, Menlo Park, CA), which involves a clip that is inserted into the mitral valve via percutaneous femoral venous transseptal access. The device is then aligned above the valve in order to secure the mitral leaflets.
All participants had moderate-to-severe (3+) or severe (4+) chronic MR. The investigators placed 1 clip in 65 patients and 2 clips in 31 patients. The remaining 11 patients did not receive clips because of an inability to reduce MR or transseptal complications. Two patients who had 1 clip implanted later underwent a second procedure to have another clip placed.
Acute procedural success was attained in 74% of patients, and 64% were discharged with MR ≤ 1. Among successfully treated patients, 66% survived, did not require mitral valve surgery, and did not have an MR > 2+ after 12 months of follow-up. Kaplan-Meier analysis revealed that 95.9% of patients were free from death at 1 year, 94.0% at 2 years, and 90.1% at 3 years. In addition, rates of freedom from surgery were 88.5%, 83.2%, and 76.3% at 1, 2, and 3 years, respectively.
PROSPECT
The first large-scale, prospective natural history study of atherosclerosis to use multimodality imaging, PROSPECT included 700 patients with ACS who underwent successful PCI in 1 or 2 major coronary arteries at 37 centers in the United States and Europe. The investigators performed quantitative coronary angiography (QCA) of the entire coronary tree, IVUS, and virtual histology (VH).
After 3.4 years of follow-up, culprit lesions (those originally treated) and non-culprit lesions (untreated areas of the coronary tree which were expected to remain stable) led to similar levels of MACE, a composite of cardiac death, cardiac arrest, MI, unstable angina, and increasing angina. Half of the events occurred within 1 year and half between 1 and 3 years.
Baseline clinical and angiographic factors were poor predictors of non-culprit lesion-related events. IVUS characteristics and VH plaque type, however, were much more informative. Among them, multivariable analysis found 3 independent predictors of lesion-level events:
- Plaque burden at the minimal luminal area ≥ 70% (OR 4.99; 95% CI 2.54-9.79; P < 0.0001)
- VH-thin cap fibroatheroma (OR 3.00; 95% CI 1.68-5.37; P = 0.0002)
- Minimal luminal area ≤ 4.0 mm2 (OR 2.77; 95% CI 1.32-5.81; P = 0.007)
According to the study investigators, the combination of large plaque burden detected by IVUS and a large necrotic core without a visible cap (ie, a VH-thin cap fibroatheroma) identifies lesions that are at especially high risk for future adverse cardiovascular events.
Commentary
Ted Feldman, MD
Evanston Hospital
Evanston, IL |
 |
Approval by the FDA panel of the Atritech Watchman Device represents a major milestone for 2009 (see story). The publication of the trial results (see story) and the growing experience with this device in the Continued Access Registry have demonstrated that a device alternative to warfarin therapy has a clear place in the treatment armamentarium. While the trial was a noninferiority trial, a major clinical result is the virtual elimination of intracranial hemorrhage in the device arm. The potential to use a device with a one-time risk for complications associated with the procedure as an alternative to the ongoing major bleeding complication rate of 2% to 4% per year with warfarin therapy for A-fib is a great achievement.
Importantly, most of the patients in the trial were at low risk for stroke and, because of their demographics, were at similarly low risk for bleeding complications from warfarin. Since the trial was positive even in this low-risk group, the potential for greater net benefit in patients at higher risk for bleeding will hopefully be demonstrated in future trials. The ongoing experience with the device in the Continued Access Registry has demonstrated a decreasing rate of procedure-related complications. Device-related perforation has diminished greatly compared to the experience reported in the randomized trial.
Another landmark for the calendar year is the publication of the Evalve MitraClip Registry results (see story). Outcomes for over 100 patients at 1 year, and for many up to 3 years, have demonstrated a freedom-from-reoperation rate of about 80% among patients successfully treated with the MitraClip. The complication profile of the device is similar to that of other percutaneous procedures such as PCI with stenting. The completion of the randomized trial comparing percutaneous clip therapy with surgical mitral valve repair or replacement is a landmark, as well. Final enrollment in the trial and 1 year follow-up were completed in calendar 2009, with final results to be reported in the first part of 2010. This represents the first percutaneous therapy for any valve lesion to complete a pivotal trial, and, importantly, also represents one of the first prospective, multicenter, core lab, and events committee-adjudicated evaluations of heart valve surgery. The results will thus be both important for the development of percutaneous mitral valve therapy and for a clear look at the state of the art of mitral valve surgery.
Ajay J. Kirtane, MD, SM
Columbia University Medical Center
New York, NY |
 |
PLATO (see story 1, story 2) was important because it marks a departure from the standard of clopidogrel, a trend that continued with the approval of prasugrel (see story).
BARI 2D is important because it continues to expand the data on revascularization for stable CAD (see story).
Completion of enrollment for the randomized PARTNER trial was a significant event in 2009. This is the pivotal US study comparing percutaneous aortic valve intervention to conventional (surgical) aortic valve replacement for high-risk patients with aortic stenosis. The trial results are anticipated next year, but the completion of enrollment in this landmark study is a harbinger of an expanded role for interventionalists in the realm of structural heart disease. The presentation of the PROTECT-AF study in atrial fibrillation (comparing the use of a device to occlude the LAA to conventional anticoagulation) in addition to the ongoing investigation of the E-valve procedure are 2 other examples of the burgeoning nature of structural heart intervention.
Robert S. Schwartz, MD
Minneapolis Heart Institute
Minneapolis, MN |
 |
Stroke is the third leading cause of mortality and disability, with 780,000 cases yearly. A major cause is cardiac emboli in patients with A-fib. Twenty-five percent of Americans over 40 will develop A-fib during their lifetime, and stroke occurs annually in 5% of A-fib patients, increasing with age. A-fib is the likely cause of stroke in 25% of patients > 80 years old.
The LAA has been suspected as the major cause of cardioembolic stroke. This hypothesis was proven this year, as was the hypothesis that mechanical obliteration of the LAA is at least equivalent to warfarin therapy and probably superior in preventing stroke and complications.
In PROTECT-AF, noninferiority of device-based LAA obliteration was proven in terms of both stroke prevention and safety, and percutaneous LAA obliteration was demonstrated to be a safe and effective alternative to warfarin. PROTECT-AF also strongly suggests that the LAA is the major source of cardiac emboli in A-fib.
William A. Gray, MD
Columbia University Medical Center
New York, NY |
 |
The continued refusal of the Centers for Medicare and Medicaid Services to pay for FDA-approved carotid stenting in the high surgical risk asymptomatic population, in spite of multiple published data showing excellent outcomes that meet or exceed AHA CEA guidelines (Capture 2/EXACT [see
story] and SAPPHIRE Worldwide from 2008 [see
story]), represents one of the major developments of 2009. Others include:
- The ASTRAL trial, published in NEJM in spite of significant “fatal” flaws in its construct and conduct that severely limit its interpretation, only further muddies the renal stent data available for patient and operator decision-making (see story).
- Positive and striking results from renal artery sympathetic radio-frequency ablation published in Lancet, with durability proven to 1 year (see story).
- Medtronic launches an interventional trial using DES to address vascular causes of erectile dysfunction.
- VIBRANT (Viabahn Versus Bare-Nitinol Stent) trial data presented at the annual Vascular InterVentional Advances (VIVA) conference, held October 19-23 in Las Vegas, NV, showing no significant differences in restenosis between bare nitinol stents and Viabahn covered stent, although the patterns of restenosis were different between groups. Another covered stent design from WL Gore changing the leading edge of the device (where most of the failures occurred) hopes to improve on the VIBRANT outcomes/findings.
Bernard J. Gersh, MB, ChB, DPhil
Mayo Clinic
Rochester, MN |
 |
BARI 2D is an extremely important and complex trial. The bottom line is that in type 2 diabetics undergoing an evaluation of CAD (a majority of whom had chronic stable angina but approximately 20% of whom were asymptomatic with positive stress tests), all of whom were randomized after angiography, 5-year survival did not differ significantly between the revascularization and medical therapy groups. In those receiving CABG, there was a reduction in the rates of nonfatal MI. In patients randomized to insulin-sensitization therapy vs. insulin-provision therapy, the rates of cardiovascular events were not different.
As was the case with the COURAGE trial, the results of BARI 2D have featured heavily in the media, resulting in a diversity of comments from individuals and professional societies.
To my mind, the results are quite clear-cut, and although no trial is perfect, this is an excellent trial which adds substantially to our body of knowledge. BARI 2D enrolled 2,368 patients, which makes it one of the largest trials of revascularization vs. medical therapy. It should be emphasized that such trials are hard to perform, and large trials with 5,000 to 10,000 patients are probably impractical in the setting of revascularization therapies for chronic stable angina. The lack of a survival difference is entirely consistent with COURAGE and other trials of revascularization vs. medical therapy alone in chronic stable angina.
The event rates of approximately 23% at 5 years suggest that this is probably a subgroup at medium risk, which is similar to COURAGE. As is the case with other studies, patients with high-risk anatomy as defined at angiography were excluded. In the revascularization group, patients undergoing PCI were at lower risk compared with CABG, and this is appropriate and reflects clinical practice with regard to patient selection. Critics might point to the fact that for part of this trial, DES were unavailable, but this should not affect the results at all since DES have not been shown to reduce death in MI but to reduce the frequency of restenosis, which was not an endpoint in BARI 2D.
The fact that all patients underwent angiography limits the generalizability of the results to patients with type 2 diabetes and coronary disease. Nonetheless, this is a fact of life that is common to most revascularization trials. Finally, the trial is not a comparison of PCI and CABG since the choice of revascularization was left to the discretion of the physician, and baseline characteristics of the 2 groups are very different. I suspect that controversy and disagreements of opinion will continue, but to my mind this is a rather emphatic neutral trial.
Sources:1. US Food and Drug Administration. Proceedings from the Circulatory System Devices Panel Advisory Meeting; April 23, 2009; Gaithersburg, MD.
2. Holmes DR, Reddy, VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: A randomised noninferiority trial. Lancet. 2009;374:534-542.
3. Feldman T, Kar S, Rinaldi M, et al. Percutaneous mitral repair with the MitraClip system: Safety and midterm durability in the initial EVEREST (Endovascular Valve Edge-to-Edge REpair Study) cohort. J Am Coll Cardiol. 2009;54:686-694.
4. Stone GW. PROSPECT: A natural history study of atherosclerosis using multimodality intracoronary imaging to prospectively identify vulnerable plaque. Paper presented at: Transcatheter Cardiovascular Therapeutics 2009; September 25, 2009; San Francisco, CA.
5. Steg, PG. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with ST-elevation acute coronary syndromes: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Trial. Paper presented at: American Heart Association Scientific Sessions 2009; November 15, 2009; Orlando, FL.
6. Cannon, CP. PLATO INVASIVE: A prospective, randomized, placebo-controlled trial of ticagrelor vs. clopidogrel in patients with ACS managed with an invasive strategy. Paper presented at: Transcatheter Cardiovascular Therapeutics 2009; September 24, 2009; San Francisco, CA.
7. US Food and Drug Administration. FDA Approves Effient to Reduce the Risk of Heart Attack in Angioplasty Patients. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm171497.htm. Accessed July 10, 2009.
8. BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009:360:2503-2515.
9. Gray WA, Chaturvedi S, Verta P. Thirty-day outcomes for carotid artery stenting in 6,320 patients from two prospective, multicenter, high surgical risk registries. Circ Cardiovasc Intervent. 2009;Epub ahead of print.
10. Gurm HS, Yadav JS, Fayad P, et al. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med. 2008;358:1572-1579.
11. The ASTRAL investigators. Revascularization versus medical therapy for renal-artery stenosis. N Engl J Med. 2009;361:1953-1962.
12. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: A multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275-1281.
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