Should Low/Intermediate-Risk Patients Be Treated with TAVR or SAVR?

As it turns out, 2015 was quite the interesting year for transcatheter aortic valve replacements (TAVR). We now know from the PARTNER trial that mortality from the first to the fifth year is much the same whether high-risk patients with aortic stenosis (AS) undergo TAVR or surgical aortic valve replacements (SAVR).¹

Also, the same team who previously reported a survival advantage with a self-expanding transcatheter bioprosthesis compared with SAVR in patients at increased risk for surgery offered 2-year results in 2015.² Reardon et al. showed not only persistence of the 1-year results of their randomized trial but a further separation of the mortality curves: the absolute reduction in risk increased from 4.9 percentage points at year 1 to 6.5 percentage points in mortality at year 2 in favor of the self-expanding valve. Thus, the reduction in overall mortality between TAVR and SAVR, which was of uncertain significance in the 1-year data, is now confirmed with a p value of 0.04.

Is this a class effect that would apply to balloon-expandable valves, too? In an accompanying editorial to the Reardon paper,³ Ron Waksman, MD, FACC, and Augusto D. Pichard, MD, FACC, noted that for patients in the PARTNER trial at high risk for surgery, randomization to balloon-expandable valves was associated with an early survival benefit over surgery that was lost early on; between 1 and 2 years, the survival curves were similar.

Nevertheless, Waksman and Pichard added that additional PARTNER data published in 2015 support the class effect argument.⁴ In comparing balloon-expandable valves versus SAVR, investigators found that for patients with no or trace paravalvular regurgitation, there was a reduction in mortality in the balloon-expandable valves with transfemoral access compared with SAVR over a 5-year follow-up (45.2% vs. 60.9%), emphasizing the need to eliminate paravalvular regurgitation post-procedure.

Moving to the Intermediate-risk Patient

Two randomized trials, designed to answer the question of safety and efficacy of TAVR in intermediate-risk patients, began enrollment a few years ago. PARTNER 2A completed enrollment in 2014 with results expected in 2016. The SURTAVI (Surgical Replacement and Transcatheter Aortic Valve Implantation) trial, which has a similar design but involves a self-expanding valve rather than the balloon-expandable valve used in PARTNER 2A, is continuing enrollment (as of Oct. 2015).

However, preliminary data are now available from a third study: Thyregod et al. recently reported their comparison of TAVR versus SAVR in an all-comers population above the age of 70 years.⁵ The Danish and Swedish investigators conducted the first randomized trial in lower-risk AS patients. The NOTION (Nordic Aortic Valve Intervention) trial, funded by the Danish Heart Foundation, retained 96% of patients at 1-year follow-up and used Valve Academic Research Consortium-2 definitions for endpoints.

The combined primary endpoint was all-cause mortality, stroke, and MI at 1 year, which was similar in both groups. Individually, all-cause mortality, stroke, MI, and new-onset or worsening atrial fibrillation (AF) rates were not significantly different but were numerically lower in TAVR patients. Major life-threatening or disabling bleeding, cardiogenic shock, and acute kidney injury were significantly lower in the TAVR group compared with the surgical cohort, but surgery appeared to be safer in terms of major vascular complications and the need for a permanent pacemaker.

In an accompanying editorial comment,⁶ E. Murat Tuzcu, MD, FACC, Samir R. Kapadia, MD, FACC, and Lars G. Svensson, MD, PhD, FACC, noted several limitations that make the findings less than conclusive. During a period of approximately 3.5 years, 1,576 patients in three hospitals were evaluated by heart teams, but only 280 patients were included in the study (mean age: 79 years). They wrote in JACC, “It is difficult to describe a study that enrolled < 20% of screened patients as an all-comers trial.” Also, the NOTION study was designed to test TAVR’s superiority with sample size calculated on the assumption that primary outcome would occur three times more frequently in the SAVR cohort. Given the similar outcomes, the editorial writers concluded, “It turns out that NOTION is an underpowered study that provides valuable but not definitive data.”

Where does that leave us?

Tuzcu and colleagues advise waiting for the results of the randomized trials of intermediate-risk patients and continue to carefully evaluate outcomes in lower-risk patients, including those treated with new-generation valves. In addition to registry studies and randomized clinical trials, heart teams should track their own institutional outcomes, local resources, and capabilities while answering the question, “What is the best treatment for our patient?” Waksman and Pichard noted that the majority of surgeons are currently embracing TAVR and converting SAVR cases to TAVR as part of the heart team approach, making the possibility that TAVR will become mainstream therapy a reality. Still, they noted, TAVR via femoral access should be considered as the first-line therapy for patients with severe aortic stenosis who are at an increased risk for surgery. SAVR should be considered only for patients who are not suitable for TAVR or for whom the data are not yet available; specifically, intermediate- and low-risk PARTNER 2A and SURTAVI patients, where we will have data soon—likely later this year.

References:

1. Mack MJ, Leon MB, Smith CR, et al. Lancet. 2015;385:2477-84.
2. Reardon MJ, Adams DH, Kleiman NS, et al. J Am Coll Cardiol. 2015;66:113-21.
3. Waksman R, Pichard AD. J Am Coll Cardiol. 2015;66:122-4.
4. Mack MJ, Leon MB, Smith CR, et al. Lancet. 2015;385:2477-84.
5. Thyregod H, Steinbrüchel D, Ihlemann N, et al. J Am Coll Cardiol. 2015;65:2184-94.
6. Tuzcu E, Kapadia SR, Svensson LG. J Am Coll Cardiol. 2015;65:2195-7.

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Transradial Versus Transfemoral Access in Patients with ACS Undergoing Invasive Management

Technically more demanding? Of course, but authors of a new study that evaluated radial vs. femoral access in patients with acute coronary syndrome (ACS) believe their results should prompt a re-evaluation of clinical guidelines and that transradial should be the preferred approach for most catheter-based heart procedures.

Compared with the femoral, the radial artery is more superficial and has a smaller calibre. This characteristic makes access site hemostasis more predictable, but procedures done via the radial artery technically demanding. Previous studies have come to differing conclusions with regards to the role of radial access in reducing adverse outcomes in patients with ACS.

According to Marco Valgimigli, MD, PhD, Erasmus University Medical Center, the Netherlands: “The radial artery is 2 mm in size, the femoral artery is probably 20 times greater than that; so the difficulties from a technical standpoint that you can face when you do complex procedures are much, much bigger with the transradial approach.”

Having said that, he thinks the results of a new randomized study “should compel a switch to the radial approach” as the preferred method. The study, dubbed MATRIX Access (Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX), randomly assigned more than 8,400 patients at 78 hospitals in four European countries to undergo angiography via the arm or the groin.1 All study participants had ACS.

There was a 15% relative risk reduction for major adverse cardiac events (MACE; 9.8% vs. 11.7%), which would have been significant at a nominal 5% alpha, but was not significant at the pre-specified alpha of 2.5%. Significance was achieved for the co-primary endpoint (MACE plus bleeding). So, differences between groups were driven by reductions in 30-day Bleeding Academic Research Consortium (BARC) major bleeding (any BARC 3 or 5 bleeding, rate ratio: 0.67; p = 0.013; access site bleeding, rate ratio: 0.37; p = 0.0004) and all-cause mortality (rate ratio: 0.72; p = 0.045). There was no difference with respect to rates of MI or stroke, which should still be reassuring given early concerns that radial access might increase cerebrovascular embolization.

As part of their paper (simultaneously published in The Lancet), Valgimigli and colleagues updated their meta-analysis of all ACS trials that randomly assigned patients to radial or femoral access after the landmark RIVAL (RadIal Vs femorAL access for coronary intervention) study. They demonstrated a “statistically robust” (rate ratio: 0.72; p = 0.0011) and “clinically relevant” reduction in all-cause mortality by radial compared with femoral access.

“Interventional cardiologists who are experienced with the radial approach have nothing to lose and everything to gain by using the arm as the access point for these procedures,” said Dr. Valgimigli.

Commenting on the study, David Kandzari, MD, FACC, director of interventional cardiology and chief scientific officer at Piedmont Heart Institute, Atlanta, GA, said, “We know that the performance of radial intervention is variable across different geographies and one end of the spectrum is the United States where it still represents less than 20% of all PCI procedures. I think this trial further motivates radial access to be the default strategy for PCI.”

Antithrombotic Analysis

The ambitious MATRIX study was designed to answer two other questions beyond percutaneous coronary intervention (PCI) access site. The investigators also wanted to determine whether there are differences in outcome between patients who receive bivalirudin and those who receive heparin before angiography and anticipated PCI. Finally, they asked, is prolonging a bivalirudin infusion for 4 to 6 hours after PCI beneficial?

They randomly assigned 7,213 of the MATRIX patients with an ACS and for whom PCI was anticipated to receive either bivalirudin or unfractionated heparin (UFH) with discretionary use of glycoprotein IIb/IIIa inhibitors. Patients in the bivalirudin group were subsequently randomly assigned to receive or not to receive a post-PCI bivalirudin infusion.

The results of this part of the trial have now been published, too.² MACE rate was not significantly lower with bivalirudin than with heparin (10.3% and 10.9%, respectively; p = 0.44), nor was the rate of net adverse clinical events (11.2% and 12.4%, respectively; p = 0.12). Post-PCI bivalirudin infusion, versus no infusion, did not significantly decrease the rate of urgent target vessel revascularization, definite stent thrombosis, or net adverse clinical events (11.0% and 11.9%, respectively; p = 0.34).

Overall, there were no significant between-group differences in the rates of BARC or TIMI bleeding, whereas the rates of BARC 3 or 5 or GUSTO bleeding were lower in the group that received post-PCI bivalirudin than in the group that did not receive a post-PCI infusion.

The authors noted, “Our results reinforce the concept that reducing the rate of major bleeding events among patients with acute coronary syndromes who are treated with PCI does not necessarily affect the risk of major ischemic adverse cardiovascular events.”

The use of radial or femoral access, which was (as noted) randomly assigned, did not prove to be an effect modifier in the bivalirudin group for any of the major outcomes. UFH was administered according to guidelines, at a mean dose of 78 units per kilogram in the control group. Hence, the results do not support the concern that the bleeding benefit in the bivalirudin group is attributable to routine use of femoral access or a high heparin dose in control patients.

New Meta-analysis

Here’s an update on the issue of femoral versus radial access. In late 2015, the results of a meta-analysis were published giving further support to the radial approach.³ Investigators identified 17 randomized trials, including four high-quality, multicenter studies of 17,133 patients. Pooled data from the four trials showed that radial access was associated with less major bleeding (relative risk [RR]: 0.57; p = 0.011), fewer MACE (RR: 0.86; p = 0.025), and even a significant reduction in all-cause mortality (RR: 0.73; p = 0.003).

Radial procedures lasted slightly longer (standardized mean difference, 0.11 minute) and had higher risk for access-site crossover (6.3% vs. 1.7%) than did femoral procedures.

Michael Savage, MD, FACC, director of the angioplasty center at Thomas Jefferson University Hospital in Philadelphia, PA, was co-author of an accompanying editorial.4 He noted that radial access is more technically challenging than femoral access.

“There are a number of reasons why doctors in the United States are slower to adopt it,” said Dr. Savage. “Even in the meta-analysis, the need to use an alternative access site is about fourfold higher in the radial artery group than the femoral group, even in centers that are fairly proficient in radial access. So, there are some trade-offs.” Also, he and his editorial co-authors noted that transradial catheterization has been shown to reduce mortality only in patients with ST-elevation MI (STEMI) and not for those with other types of ACS or in stable patients undergoing elective PCI. (In RIVAL, for example, there was a trend toward higher mortality in radially-treated patients.)

But the arm artery’s location close to the skin in the wrist and its ready “compressibility” make it easier to reduce any procedure-related bleeding there than at the groin artery.

Dr. Savage and coauthors wrote, “This (meta-analysis) adds to the mounting evidence of the clinical benefits of radial access and, hopefully, it will spur U.S. cardiologists to catch up to their international colleagues in greater adoption of this approach.”

References:

1. Valgimigli M, Gagnor A, Calabró P, et al. Lancet. 2015;385:2465-76.
2. Valgimigli M, Frigoli E, Leonardi S, et al. N Engl J Med. 2015;373:997-1009.
3. Andò G, Capodanno D. Ann Intern Med. 2015 Nov. 10 [Epub ahead of print]
4. Savage MP, Fischman DL, Ruggiero NJ. Ann Intern Med. 2015 Nov. 10 [Epub ahead of print]

Clinical Topics: Acute Coronary Syndromes

Keywords: CardioSource WorldNews Interventions, Acute Coronary Syndrome, Bioprosthesis, Cardiac Catheterization

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