What Interventional Trials Impact Your Practice?

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In an effort to assess which clinical trials have had the greatest impact on cath lab practices today, Cardiovascular Business polled six leading interventional cardiologists about which trials they would designate as the biggest gamechangers.

The participants are:

  • Harold L. Dauerman, MD, Director of Cardiovascular Cath Labs at the University of Vermont (UVM) in Burlington,Vt.
    Top Picks: FAME, HORIZONS-AMI, SPIRIT IV, SYNTAX
  • Stephen G. Ellis, MD, Section Head, Invasive and Interventional Cardiology at Cleveland Clinic.
    Top Picks: FAME, HORIZONS-AMI, PLATO, PARTNER, SYNTAX
  • David R. Holmes, Jr., MD, President of the American College of Cardiology; Interventional Cardiologist at Mayo Clinic in Rochester, Minn.
    Top Picks: PARTNER, PLATO, PROTECT-AF, TRITON-TIMI
  • Gregg W. Stone, MD, Director of Cardiovascular Research at New York-Presbyterian Hospital/Columbia Medical Center in New York City.
    Top Picks: FAME, HORIZONS-AMI, PLATO, PARTNER, SYNTAX
  • Christopher J. White, MD, President of the Society of Coronary Angiography Interventions; Chairman of the Department of Cardiovascular Diseases, Ochsner Health System in New Orleans.
    Top Picks: FAME, HORIZONS-AMI, PLATO, PARTNER, SYNTAX
  • Alan C. Yeung, MD, Director of Interventional Cardiology, Stanford University Medical Center in Stanford, Calif.
    Top Picks: FAME, PARTNER, RESOLUTE/ENDEAVOR, SYNTAX

Surprisingly, the selected trials focused less on stents themselves, but rather, on how physicians decide which patients and lesions are most appropriate for stenting, and which are not. The adjunctive pharmacologic approach to PCI also garnered attention, with the expanding antiplatelet choices and the confirmed bleeding reduction with bivalirudin. Of course, the potential for transcatheter aortic valve replacement (TAVR), while not currently available in U.S. cath labs, is already on the forefront of their minds as well.

FAME gets more famous

The most commonly chosen trial was FAME, which assessed 1,005 patients with multivessel coronary artery disease (CAD), who were randomized to multivessel PCI guided by fractional flow reserve (FFR), compared with PCI guided by angiography alone (N Engl J Med 2009;360:213-224). Tonino et al reported a 30 to 40 percent decrease in cardiac events, including death, MI and the need for repeat stenting or bypass surgery in the FFR arm. Also, researchers reported that patients who received the additional blood flow test received one-third fewer stents than the group examined only with an angiogram.  

White calls FAME "the biggest gamechanger," while Ellis credits the trial with "bringing physiology into the cath lab," as opposed to basing the science of interventional cardiology solely on anatomic assessment of the patient.    

Performing FFR provides "confidence in the cath lab that can appropriately inform us whether a particular lesion is significant or not," Yeung says. "Conversely, a positive stress test often doesn't tell us which lesion is most responsible."

"The use of physiology-guided stenting," says Ellis, "has become our standard for measuring indeterminate lesions or figuring out whether it's physiologically important. Sometimes that leads to intervention, sometimes not. If a physician measures FFR and wants to be aggressive, 0.8 can be the cutoff."

Interventional cardiology is in the hot seat, due to several highly publicized cases of stenting overutilization. "Our physicians are under scrutiny to ensure their procedures are appropriate in patients with stable coronary disease, and we need evidence of ischemia in either noninvasive or an invasive test to know that intervention is the appropriate pathway," Stone says.

Despite the clamoring for complete appropriate use criteria (AUC) adherence, White says that "AUC is a tool, but not a means to an end. When you attempt to codify those behaviors, it sometimes disregards good clinical judgment. AUC should be used as a measurement of variation, and physicians should not be afraid of it, but instead, use the tool to improve care.   

"As we have become more quality conscious as a specialty, we also have become more cost conscious," White says. "FAME is a cost-effective pathway to achieve the highest quality outcomes."

From an economic perspective, a FAME substudy found that the overall mean costs at one year were significantly less in the FFR-guided arm ($14,315 vs. $16,700) (Circulation 2010;122[24]:2491-2633). A bootstrap simulation indicated that the FFR-guided strategy was cost saving in 90.74 percent of the 1,005 patient cases and cost effective at a threshold of $50,000 per quality-adjusted life-years in 99.96 percent. Fearon et al reported that the procedural costs accounted for approximately 70 percent of the cost savings, and the follow-up event rates accounted for about 30 percent of the savings.

Conversely, Dauerman says that the procedure does cost more money, and does not result in greater reimbursement, but "we don't care because we're using the technology for the clinical benefits associated with appropriate lesion selection."

Despite the nearly uniform assertion about FAME, the utilization of FFR remains relatively low across the U.S. Cleveland Clinic uses FFR in 25 percent of its elective PCI cases, UVM uses the technology about 20 percent and Stanford approximately 15 to 20 percent. "While there has been a major shift, it's not a wholesale change in practice," Ellis says.

U.S. adoption would be driven upward if the guidelines recommended the treatment of physiologic assessment, according to Dauerman, in a similar fashion to the European guidelines.

SYNTAX in context

The SYNTAX study compared CABG with PCI using drug-eluting stents (DES) in 1,800 patients with three-vessel or left-main CAD from 62 sites in Europe and 23 sites in North America who were randomly assigned in a 1:1 ratio (N Engl J Med 2009;360:961-972). One-year results showed that the rates of major adverse cardiac or cerebrovascular events—the study's primary endpoint—were significantly higher in the PCI group than the CABG group (17.8 vs. 12.4 percent). At 12 months, the rates of death and MI were similar between the two groups; stroke was significantly more likely to occur with CABG (2.2 vs. 0.6 percent with PCI).

In a later economic analysis of SYNTAX, presented at ACC.09, Cohen et al found that both stenting and CABG improved the overall quality of life over one year of follow-up, although chest pain relief was slightly better with CABG. Also, in the U.S. healthcare system, surgery was initially about $6,000 (or about 25 percent) more costly than PCI, reflecting higher hospital costs and much higher physician fees. However, PCI added approximately $2,500 in follow-up costs over the following year, mainly due to additional heart procedures and the need for long-term antiplatelet medication.

"SYNTAX has redefined the way we think about treating complex CAD, showing that stent technologies are limited in patients with triple-vessel CAD," Stone says. "While we learned that certain patients should be diverted from PCI to surgery, the trial also opened the whole field of elective left-main PCI for patients with low to moderate SYNTAX scores."

Going one step further, Dauerman states that the trial "has taken away the death penalty association of diabetes and multivessel disease with stenting, which was previously perceived through the results of the BARI trial." He adds that one caveat to the findings is the overall performance of the paclitaxel-eluting stent (Taxus, Boston Scientific) used in SYNTAX may be less than that of the second-generation everolimus-eluting stent (Xience, Abbott Vascular), so the "absolute numbers that we quote to patients from this trial may be slightly off compared with contemporary clinical practice, but it's the best estimate we have at this time."   

While use of the actual SYNTAX score, which is now available online, in clinical practice is admittedly "low, it will increase over time," Stone says. He adds that the EXCEL trial, in which Stone is the co-principal investigator, is enrolling patients with mild to moderate anatomic complexity (SYNTAX score of less than or equal to 32) employing the Xience stent, and will get another 150 to 200 sites to use the score on a regular basis.

"Since I'm not able to calculate the score in my head, and the use of internet-based technologies in the cath lab is minimal, I instead base my decision on the diffuseness of coronary disease as a marker for the SYNTAX score," Dauerman says.

Some have suggested that applying the logic of SYNTAX in the cath lab and utilizing FFR technology in the cath lab could drive down the use of stents. In fact, that is what Ellis has witnessed: "Cath lab volumes are down quite a bit, and nationwide, physicians have gotten more conservative, particularly for elective PCI. You could almost argue that they are too low, but that is the trend."  

However, Dauerman has not experienced the same downward trend, suggesting that FFR allows interventionalists to better classify a patient who would have previously been identified with three-vessel disease, and sent for bypass surgery. "If the FFR is non-ischemic in one or two of those vessels, you are converting that patient to one with single-vessel, which is likely to confer all of their ischemic risk," he says. "Anecdotally, my personal PCI volume has been exactly the same for the past 10 years. For instance, SYNTAX hasn't changed which of my patients with multivessel disease undergo PCI, but it allows me to better communicate potential outcomes and risk."

Another trend that emerged from SYNTAX: Collaboration is key. "SYNTAX stressed the importance of the heart team approach, encouraging the surgeon and interventionalist to communicate about patients with complex cardiac disease to choose the right revascularization modality. In that regard, it has been a landmark study," Stone says.

Antiplatelets get less sticky

For the last five years, there has been increased attention paid to stent thrombosis. However, next-generation stents and newer dual-antiplatelet drugs have driven down its rates.

"Although stent thrombosis affects a very small percentage of patients, when it does occur, it can be catastrophic with 40 to 60 percent of patients dying from MI," Holmes says. "There are several different trials, beginning with the TRITON-TIMI 38 trial, built on the understanding that there are genetic differences in how people respond to clopidogrel [Plavix, Bristol-Myers Squibb/Sanofi-Aventis], and we began to understand that a specific family of genes could adversely impact the absorption and metabolism of clopidogrel."

TRITON-TIMI 38 enrolled 13,608 patients with acute coronary syndromes (ACS) with scheduled PCI, comparing prasugrel (Effient, Eli Lilly/Daiichi-Sankyo) with the standard-dose clopidogrel (N Engl J Med 2007;357:2001-2015). The primary efficacy endpoint occurred in 12.1 percent of patients receiving clopidogrel and 9.9 percent of patients receiving prasugrel. In a later economic substudy of TRITON-TIMI 38, presented at TCT.09, Cohen et al found that prasugrel was associated with a $221 reduction for total hospital costs.

Although prasugrel was associated with higher rate of life-threatening bleeding, the FDA approved this new thienopyridine for the U.S. market as an alternative to clopidogrel in June 2009.

While additional antiplatelet agents have been tested and assessed, only ticagrelor (Brilinta, AstraZeneca) has shown a mortality benefit, resulting in FDA approval in July after one year of regulatory delays.   

The PLATO trial, which compared ticagrelor and clopidogrel for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an ACS, with or without ST-segment elevation, showed that ticagrelor significantly reduced the rate of death from vascular causes, MI or stroke without an increase in the rate of overall major bleeding, but with an increase in the rate of non-procedure-related bleeding (N Engl J Med 2009;361:1045-1057).

PLATO showed that "compared with clopidogrel, ticagrelor, which has tremendously increased efficacy in preventing peri-procedural MI and stent thrombosis, while not increasing life-threatening or fatal bleeding, also can improve survival in patients with ACS," Stone says.

These newer drugs, such as prasugrel and ticagrelor, "have different advantages, compared with the standard drug of clopidogrel, and now have achieved Class 1 indications for at least certain patients with ACS," says Holmes. "These drugs will change the field because they improve outcomes in patients for whom we were giving older therapy. Also, these drugs offer the opportunity to avoid some of the genetic interference with uptake and metabolism of the older drugs. Thus, they are more reproducible, and more predictable."  

How will these new antiplatelet options play out for patients? "For clopidogrel, prasugrel and ticagrelor to make the decisions, you need to have a personalized approach, but because prasugrel and ticagrelor have an increased bleeding profile, they should be avoided in patients with an active bleeding diathesis, as well as in patients with recent stroke or transient ischemic attack," Stone says. "It needs to be individualized decision making; it can't just be a one-size-fits-all category." He also cautioned use of the newer drugs in patients with low body weight and those on warfarin.  

In terms of adoption rates, "prasugrel's uptake was a little slower than it should have been because of concerns of life-threatening and fatal bleeding, but those could have been mainly overcome through an individualized approach," Stone continues "Ticagrelor doesn't quite have that concern, so I predict its use will be more widespread."

HORIZONS provides a look beyond bleeds

The three-year results of the HORIZONS-AMI trial, presented at TCT.10, which tracked 3,602 randomized STEMI patients, showed the administration of bivalirudin (Angiomax, The Medicines Company) enhanced survival compared with the use of heparin plus a glycoprotein IIb/IIIa (GpIIb/IIIa) inhibitor in STEMI patients undergoing primary PCI. The trial also found that the use of a paclitaxel-eluting stent was shown to be as safe and more effective than a bare-metal stent at three years.

"HORIZONS-AMI, as well as the ACUITY trial, showed that the previous anticoagulation regimen standard—the gold standard of heparin and a glycoprotein IIb/IIIa antagonist—was not the best adjunctive medical regimen for patients undergoing PCI," Ellis says. "Furthermore, the interest spawned by the results brought awareness to the importance of bleeding as an adverse prognostic factor over the long haul. These two studies, in particular, established bivalirudin as the new gold standard, which almost overnight led to a wholesale shift in terms of the adjunct medicines used in our lab."

In 2005, about 94 percent of U.S. primary PCI patients received a GpIIb/IIIa inhibitor strategy, which Dauerman suggests has been cut in half, due to the net clinical benefits seen in HORIZONS-AMI.

"While there wasn't a formal cost-effectiveness analysis from HORIZONS-AMI, it has been modeled by several investigators in several countries, which will be published over the next six months, showing that it's very cost effective and in fact, economically dominant in that it's not only safer and more effective, but actually less costly," says Stone, who was the principal investigator of the trial.

The decrease in bleeding is beneficial both for clinical outcomes and for healthcare costs, as major bleeding events result in an average four- to six-day increase in length of stay, and an average increase of hospital costs by $6,000 to $8,000 (Am J Cardiol 2003;92[8]:930-935). This will become particularly relevant as CMS is threatening not to reimburse providers for preventable events in the near future.

As an example, Ellis says that a few years ago, the Cleveland Clinic's cath lab bleeding risk was between 4.5 to 5 percent with the GpIIb/IIIa strategy, and it is currently between 2 and 2.5 percent with the bilvalirudin strategy.

Promise of PARTNER

While TAVR is not yet FDA approved (as of press time), and thus, is still an investigative device in the U.S., many of the contributors choose both cohorts of the PARTNER trial as the most impactful due to the potential of the new "transformative nature of the technology," as Holmes suggests.

In Cohort B, which randomized 358 patients with aortic stenosis who were not considered to be suitable candidates for surgery, patients underwent randomization to standard therapy or TAVR (N Engl J Med 2010;363:1597-1607). At one year, the rate of death from any cause was 30.7 percent with TAVR, as compared with 50.7 percent with standard therapy. In Cohort A, Smith et al randomly assigned 699 high-risk patients with severe aortic stenosis to undergo either TAVR or surgical replacement (N Engl J Med 2011;364:2187-2198). The rates of death from any cause were 24.2 percent in the transcatheter group and 26.8 percent in the surgical group at one year, a reduction of 2.6 percentage points in the TAVR arm.

During the FDA panel meeting in July, which evaluated the patient population in Cohort B, the stroke risk was raised as the biggest concern—but the panel eventually voted to recommend the device's approval to the agency.

"The U.S. is always four or five years behind Europe and Canada because the regulations make it very difficult for us," White says. "However, if you look at Europe and Canada, it's been a major step forward in the care for the elderly."  

Yeung takes that sentiment one step further: "This technology will usher in a new era of interventional cardiology."

White suggests that the high price point and the high risk associated with the procedures will cause the CMS and the FDA to monitor the procedures very closely, potentially limiting the number who are able to receive reimbursement to certified centers. But he also predicts that the technology will continue to evolve and improve over the next 10 years, becoming much more "user-friendly."

While the future of the cath lab will certainly have to make room for the treatment of structural heart disease, all these trials have helped interventional cardiologists treat the appropriate patient with the appropriate therapy at the appropriate time.