Experts Give Their Picks for Most Important Developments of 2011

From expanded data showing the efficacy of transcatheter aortic valve replacement (TAVR) to new carotid disease treatment guidelines, 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 of 2011.

Our physician panel referenced several seminal trials and events from the past year: new PARTNER data, SYMPLICITY, ACT, and EVEREST II, as well as FDA advisory panel endorsement of the Zilver stent and new carotid disease guidelines. 

More PARTNER

The groundbreaking results at 1 year from Cohort B of the PARTNER (Placement of Aortic Transcatheter Valves) trial were maintained at 2 years, continuing to support the superiority of TAVR over standard therapy for symptomatic patients with severe aortic stenosis who are not candidates for surgery.

At TCT 2011, Raj R. Makkar, MD, of Cedars-Sinai Medical Center (Los Angeles, CA) presented the 2-year results of PARTNER (see story), which randomized 358 inoperable patients with severe aortic stenosis and cardiac symptoms to TAVR (n = 179) with the Sapien heart valve system (Edwards Lifesciences, Irvine, CA) or standard therapy.

At 2 years, cumulative rates of cardiovascular mortality, repeat hospitalizations, and New York Heart Association (NYHA) class III/IV symptoms were all lower with TAVR, while stroke rates were higher (table 1).

Table 1. PARTNER, Outcomes at 2 Years

Meanwhile, researchers presented data from Cohort A of the PARTNER trial at the American College of Cardiology (ACC) Scientific Session/i2 Summit on April 3, 2011 in New Orleans, LA (see story). Cohort A randomized 699 high-risk, operable patients with symptomatic, severe aortic stenosis to either surgery (n = 350) or TAVR (n = 348). At 1 year, the primary endpoint (mortality) was equivalent between the 2 treatments. Major strokes, however, were higher for TAVR, with the difference reaching significance when factoring in the composite of stroke/transient ischemic attack (TIA). Though major vascular complications were increased with TAVR, this difference was balanced by decreases in major bleeding and new onset atrial fibrillation (table 2).

Table 2. Clinical Outcomes at 1 Year 

^a Primary endpoint; P = 0.001 for noninferiority.

 

In addition, further analysis of Cohort A data presented at TCT 2011 on November 10, 2011, in San Francisco, CA, showed that TAVR performed via transfemoral access improves quality of life and is cost-effective in high-risk patients with severe aortic stenosis (see story).

Commentary

This past year saw a continued explosion of interest in the field of valvular heart disease.  Continued analyses and follow-up from the PARTNER trial of transcatheter aortic valve replacement were presented and published during the course of the year, solidifying the data regarding use of this technology in the management of high-risk patients with aortic valve disease. The primary results of Cohort A of the trial demonstrated similar overall mortality with both procedures at 1 year of follow-up despite better-than-expected outcomes in the surgical AVR group. These data, combined with favorable cost-effectiveness and quality of life data from the Cohort A randomization presented at TCT, firmly expand the role of TAVR to the management of patients with severe aortic stenosis who are high-risk operative candidates. 

In addition to these data in operable patients, 2-year follow-up of Cohort B of the PARTNER trial were presented at TCT. These data demonstrated a durable benefit of TAVR over medical therapy, with continued separation of mortality curves in favor of TAVR and continued benefits in NYHA class and excellent performance of the percutaneous valve as assessed by echocardiography. The results of this trial ultimately led to FDA approval of the Edwards Sapien valve system in November 2011, with commercial introduction of the valve in the United States shortly thereafter.

SYMPLICITY

Though the trial was presented at the tail end of 2010, our panel thought it was important enough to tap as one of the most important developments of 2011. Results of the Symplicity HTN-2 trial were presented in November 2010 and simultaneously published in the Lancet. The trial randomized 106 patients with treatment-resistant hypertension to undergo their existing treatment with or without radiofrequency ablation of the renal sympathetic nerves, or renal denervation, (see story).

At 6 months, the primary endpoint of office-based BP measurement had been reduced by 32/12  mm Hg from 178/96 mm Hg at baseline in the denervation group (n = 49; P < 0.0001 for systolic and diastolic BP) (see figure 1). Meanwhile, in the existing treatment group (n = 51), office-based BP only changed by 1/0 mm Hg from its baseline level of 178/97 mm Hg (P = 0.77 for systolic BP, P = 0.83 for diastolic BP). These changes resulted in an overall 33/11 mm Hg reduction in BP in the renal denervation group relative to the existing treatment group (P < 0.0001).

ACT

Results of the Acetylcysteine for Contrast-induced nephropathy Trial (ACT) were published online August 22, 2011, ahead of print in Circulation. The ACT trial randomized 2,308 patients who were undergoing either coronary or peripheral vascular angiography to 1,200 mg N-acetylcysteine (NAC; n = 1,172) or placebo (n = 1,136) given orally every 12 hours as 2 doses before and 2 doses after the procedure (see story).

At 48 to 96 hours after angiography, patients had exactly the same likelihood of developing contrast-induced acute kidney injury (primary endpoint; defined as 25% elevation in serum creatinine [SCr]), regardless of whether they received NAC or placebo. The proportions of those who experienced elevations of at least 0.5 mg/dL SCr or a doubling of SCr also were similar between groups (table 3).

Table 3. Outcomes at 48 to 96 Hours

At 30 days, clinical outcomes were equivalent in both study arms.

Commentary

Renal denervation is clearly the most promising new interventional procedure and the results of SYMPLICITY II confirmed the promise of this strategy. Uncontrolled hypertension is a leading contributor to cardiovascular mortality and morbidity worldwide and renal denervation is the first therapy that has demonstrated robust efficacy with remarkable safety for treatment of this disorder. The safety of the procedure and the technical simplicity make it quite likely that the procedure will be easily adopted into wider practice and emerge as a paradigm-changing therapy for patients with uncontrolled hypertension. Furthermore, this procedure appears to be associated with multiple other metabolic changes that are likely to positively impact cardiovascular health.

Another study that merits discussion among the most important of 2011 is the ACT trial. It is amazing that it took nearly a decade from the time that the first study on N-acetylcysteine was published to the publication of the first adequately powered trial. Hopefully, with this trial, we can put an end to the practice of offering our patients an absolutely disgusting and completely ineffective compound accompanied by the false hope that it will protect their kidneys.   

EVEREST II

Two-year results from the EVEREST II trial analyzing percutaneous repair of mitral regurgitation (MR) were presented on April 3, 2011, at the annual ACC Scientific Session/i2 Summit in New Orleans, LA, and simultaneously published in the New England Journal of Medicine. EVEREST II randomized 279 patients with moderate-to-severe or severe MR (3+ or 4+) and anatomical criteria suitable for endovascular repair to percutaneous treatment with the MitraClip system (n = 184; Evalve, Inc, Menlo Park, CA) or surgical repair or replacement (n = 95; see story).

One- and two-year findings indicated similar rates of death with the MitraClip device compared to surgery and similar MR reduction, with about 20% of all patients still having 3+ or 4+ MR. However, the primary efficacy endpoint of freedom from death, mitral valve surgery or re-operation, or 3+ or 4+ MR favored surgery, driven primarily by a significantly higher rate of surgical intervention in the percutaneous group (table 4).

Table 4. Two-Year Outcomes, Intention-to-Treat Analysis           

^aFreedom from death, MV surgery/re-operation, 3+ or 4+ MR.

Commentary

One of the important reports of 2011 in cardiovascular therapy and interventional cardiology is the publication of the 1- and 2-year outcomes of MitraClip therapy for mitral regurgitation (N Engl J Med 2011;364:1395-1406.). The report of the EVEREST 2 trial is a landmark in several respects. It is the first completed randomized trial evaluating a percutaneous therapy for mitral regurgitation and also one of the first prospective multicenter core lab adjudicated evaluations of conventional mitral valve surgery. The trial included patients with guideline class I indications for mitral valve intervention for MR.

Overall, the MitraClip device was less effective at reducing MR than surgical valve repair or replacement, but was safer and resulted in improvements in quality of life and NYHA functional class that were as good as or better than surgery. The probability a patient would be free of need for mitral valve surgery at 1 year was 80%. Subgroup analyses demonstrated that patients over age 70, those with abnormal LV function, and those with functional MR had results that were similar to surgery.

The impact of the trial is that it has established percutaneous mitral therapy as a meaningful option for selected patients with MR. The findings suggest greatest efficacy in older patients with abnormal LV function and functional MR, which reflects the usage pattern worldwide. This study defines a treatment option for a group of patients for whom there has been either no good option or no option at all.

Note: Dr. Feldman is principal investigator of the EVEREST II trial.

Zilver DES Nears Approval

The first drug-eluting stent (DES) for the treatment of above-the-knee femoropopliteal artery disease took a step closer to availability in the United States following a unanimous (11-0) vote on October 13, 2011, by a US Food and Drug Administration (FDA) advisory panel (see story).

The panel decided in favor of the polymer-free paclitaxel-eluting Zilver PTX (Cook Medical, Bloomington, IN), a self-expanding nitinol stent. The device is indicated for improving luminal diameter in de novo or restenotic symptomatic lesions with reference vessel diameters of 4 to 9 mm and total lesion lengths up to 140 mm per limb and 280 mm per patient.

The primary evidence reviewed by the Circulatory System Devices Panel included a multinational trial that randomized 479 patients with symptomatic, above-the-knee femoropopliteal disease and Rutherford class ≥ 2 to treatment with the Zilver PTX stent (n = 241) or balloon angioplasty (n = 238).

At 12 months, the primary safety endpoint of survival free of amputation, TLR, or worsening Rutherford score (by 2 classes or to class 5 or 6) was met by 90.4% of patients who received the Zilver PTX stent vs. 82.6% who underwent angioplasty (P < 0.01). In addition, the primary efficacy endpoint of patency on duplex ultrasonography or angiography, when available, was reached by a greater proportion of patients receiving the Zilver PTX than those who underwent angioplasty or provisional implantation of a BMS.

Cath Lab Quality Improvement Effort

The Society for Cardiovascular Angiography and Interventions (SCAI) unveiled a multi-pronged program aimed at improving the care delivered by cath labs nationwide. The announcement came May 5, 2011, during the SCAI 2011 Scientific Sessions in Baltimore, MD (see story).

The program consists of several key elements, among them a “toolkit” or series of measures that can be implemented and customized to individual hospitals. These include educational material regarding:

• Guidelines
• Peer review conferences
• Random case selection
• National database participation
• Pre-procedure checklists
• Data collection
• Inventory management 

New Carotid Disease Guidelines

Following a US Food and Drug Administration Circulatory System Devices Panel in favor of expanding the indication for carotid artery stenting (CAS) to patients at standard risk for surgical complications, 14 medical societies collaborated to develop a practice guideline for the management of patients with extracranial carotid and vertebral artery disease. The new recommendations view stenting as a viable alternative to surgery in many cases (see story).

According to the guidelines, published online February 1, 2011, CAS is a safe and effective alternative to carotid endarterectomy (CEA) in symptomatic patients with more than 50% stenosis and low to average surgical risk. The guidelines also state that prophylactic CAS might be considered in highly selected patients with asymptomatic carotid stenosis (minimum 60% by angiography, 70% by validated Doppler ultrasound), but add that its effectiveness compared with medical therapy alone in this situation is not well established.

Commentary

One of the major developments of the past year, the long-awaited publication of the American College of Cardiology Foundation and American Heart Association Practice Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease, is broadly endorsed by 14 professional societies including stakeholders from:

• Medicine/cardiology: American College of Cardiology, American Heart Association, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine, Society of Atherosclerosis Imaging and Prevention
• Neurology: American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons
• Radiology: American College of Radiology, American Society of Neuroradiology, Society of Interventional Radiology
• Surgery: Congress of Neurological Surgeons, Society of NeuroInterventional Surgery, Society for Vascular Surgery

The guideline was delayed to include recommendations that referenced the CREST (Carotid Revascularization Endarterectomy versus Stenting Trial) study. CREST is the largest randomized controlled trial in average surgical risk patients to compare outcomes of carotid artery stenting (CAS) to those of carotid endarterectomy (CEA). The highlight of this guideline document and a very significant advance for the field was the endorsement by the leading surgical societies of the provision stating that CAS is indicated as an alternative to CEA for average risk symptomatic patients (> 50% diameter stenosis at angiography) if the anticipated rate of periprocedural stroke or mortality is less than 6% (Class I; level of evidence: B). In addition, the document states that for asymptomatic average risk patients (> 60% diameter stenosis by angiography) CAS might be considered an alternative to surgery in highly selected patients (Class IIB; level of evidence: B; table 5).

Table 5. Level of Evidence for Guideline Recommendations

Diameter stenosis determined by angiography.

Another major development was the FDA advisory panel vote recommending approval of the Zilver stent. This was based on the Zilver PTX trial, which compared a polymer-free, paclitaxel-coated nitinol drug-eluting stent (DES) with percutaneous transluminal angioplasty (PTA) and also included a secondary comparison of provisional DES to provisional BMS placement in patients with moderate length (< 14 cm) above-the-knee femoropopliteal PAD.

Compared with the PTA group, the primary DES group exhibited superior 12-month event-free survival and primary patency, satisfying the primary hypothesis. The provisional DES group demonstrated superior primary patency (89.9% vs. 73.0%; P = 0.01) and superior clinical benefit (90.5% vs. 72.3%; P = 0.009) compared with the provisional BMS group. The authors concluded that the use of Zilver PTX in patients with moderate-length (65 ± 40 mm) above knee femoropopliteal PAD lesions is safe and associated with superior 12-month patency compared with either PTA or provisional BMS placement.

This year also saw the unveiling of the SCAI-Quality Improvement Toolkit (SCAI-QIT), a broad collection of quality improvement tools, which include implementation of guidelines and appropriate use criteria; quality benchmarking; pre-procedure checklists; peer review conferences; national database participation; and inventory management. Participants can download as many of the tools as they like at www.SCAI.org/QITChampion at no cost and are encouraged to adapt them to meet their needs. Webinars offering support for these quality improvement efforts are available at www.SCAI.org/QITWebinars. SCAI-QIT is now in use in cath labs throughout the world, with more than 230 Quality Champions represented in 34 states and 17 countries.

Note: Dr. White is president of SCAI.

 

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Sources:
1. Makkar RR. Two-year outcomes of transcatheter aortic valve replacement (TAVR) in “inoperable” patients with severe aortic stenosis: The PARTNER Trial. Paper presented at: 23rd Annual Transcatheter Cardiovascular Therapeutics Scientific Symposium; November 10, 2011; San Francisco, CA.

2. Cohen DJ. Health-related quality of life after transcatheter vs. surgical aortic valve replacement in high-risk patients with severe aortic stenosis: Results from the PARTNER trial (Cohort A). Paper presented at: 23rd Annual Transcatheter Cardiovascular Therapeutics Scientific Symposium; November 10, 2011; San Francisco, CA.

3. Reynolds MR. Cost effectiveness of transcatheter aortic valve replacement compared with surgical aortic valve replacement in patients with severe aortic stenosis: Results from the PARTNER trial (Cohort A). Paper presented at: 23rd Annual Transcatheter Cardiovascular Therapeutics Scientific Symposium; November 10, 2011; San Francisco, CA.

4. Esler MD. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): A randomized controlled trial. Lancet. 2010;Epub ahead of print.

5. ACT investigators. Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: Main results from the randomized Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT). Circulation. 2011;Epub ahead of print.

6. Feldman T, Foster R, Glower DG, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med. 2011;Epub ahead of print.

 

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