Conventional Wisdom? BAH!: Will New Evidence Cast Doubt on the Prevailing Wisdom?
The provocative notion that 'everything you know is wrong' is alluring, if not a tad exaggerated. It may do the practicing cardiologists well, however, to look at many different sides of a specific issue, particularly those for which there may be some basis in evidence. Medicine is a scientific endeavor predicated on the availability and reproducibility of evidence and the support of robust data, so not every idea or notion flies. There are, however, countervailing ideas to what might clumsily be referred to as "conventional wisdom" that have some basis in evidence, and that have no shortage of passionate advocates for that position.
To this end, CardioSource WorldNews: Interventions got in touch with a handful of researchers, interventionalists and clinicians who were willing to articulate some of these positions.
Rivaroxaban Plus DAPT: A Case of Enthusiasm Exceeding the Evidence
In this evidence-based world of cardiology, a typical response to a proclamation about a new treatment's benefits is a wary "Show me the study." However, when 60-year-old warfarin is the newest kid on the block, it's understandable why the expectations for a novel, oral clot-buster may surpass existing data.
As it stands, current data on rivaroxaban as add-on therapy for ACS are "intriguing," but not conclusive, said Matthew T. Roe, MD, MHS, associate professor of medicine with tenure at Duke Clinical Research Institute and Duke University Medical Center. "There are many unanswered questions."
There are also many lingering concerns, including a dose-dependent increased risk of bleeding found in some investigations. This highlights the delicate risk-benefit analysis required to determine ideal dose, duration, and combination of antithrombotic therapies. In a pooled analysis of the ATLAS 1 trial, where four doses of rivaroxaban were compared to placebo, there was a decrease in the incidence of death, MI, and stroke—albeit with an increase in bleeding at the higher doses. In ATLAS 2, two doses of rivaroxaban were compared to placebo (all patients were on aspirin and 93% were on thienopyridine at discharge). Again, there was a statistically significant reduction—although not a substantial decrease—in CV death, MI, and stroke. Comparing the rivaroxaban data from trials that pitted clopidogrel against prasugrel or ticagrelor, the findings, curves, and hazard ratios appear very similar, although these were not head-to-head comparisons with rivaroxaban.
Puzzling, said Dr. Roe, is that in ATLAS 2, rivaroxaban cut CV death and all-cause death, without reducing the incidence of MI. "People are struggling to figure that out," Dr. Roe said. "What is the mechanism of mortality reduction, if there's no difference in MI rates?"
Perhaps, if that missing link is discovered and results are obtained from head-to-head trials, rivaroxaban's place in the armamentarium will be better understood. "As we seek to optimize antithrombotic therapy post-ACS, we need to consider cost, bleeding risk, and long-term patient compliance," Dr. Roe added.
Rethinking DAPT Duration: In Some Cases, Less Really Is More
When it comes to dual antiplatelet therapy (DAPT) post-DES implantation, a shorter duration of treatment may prove best. In fact, the wisdom behind keeping patients on DAPT for 1 year after DES isn't based on randomized trial data, said Tullio Palmerini, MD, of the cardiovascular department at the University of Bologna, Italy.
Instead, these recommendations are based on observational studies, which have produced inconsistent and, at times, confounding results. What is clear, according to Dr. Palmerini, is that discontinuing DAPT in the first 30 days is convincingly associated with an increased risk of major adverse events. The impact of stopping the treatment in the following months, though, tells another story.
That story was edited in 2006, when data emerged linking the first-generation DES to an increased rate of death or MI. Subsequently, guidelines that originally recommended DAPT for 3 or 6 months (depending on the type of DAPT implanted) extended that recommended treatment length to a full year. That change, Dr. Palmerini said, isn't necessarily necessary.
A shorter duration of DAPT may, in fact, be sufficient to ward off major post-DES events. Trials such as ENDEAVOR OCT, DATE, and RESET indicated no difference in death, MI, and stent thrombosis in patients who were on or off DAPT at the 1-year mark. A real-world analysis of more than 10,000 patients also showed low stent thrombosis rates at 1 year, and those patients who stopped after the first quarter showed no increased risk. Therefore, recommending a shorter course of treatment may be warranted, and, in many cases, welcomed.
Newer generations of DES have added another dimension to this question, as they elute different drugs, use different polymers, and have a different platform. In certain aspects, though, newer does appear better. More recent DES don't contain polymer or contain a polymer that is biodegradable. "Second-generation DES have shown to be safer than the first-generation DES and bare-metal stents. Randomized trials are not conclusive because they were all under powered," said Dr. Palmerini, adding that further randomized trials to address this issue are warranted.
Surgery Versus Intervention for Mitral Regurgitation
Presently, repairing mitral regurgitation (MR) via surgery is the preferred option, but as an array of interventional devices to repair the mitral valve become available, surgery may soon be a thing of the past.
The devices in development will, of course, have more limited capacity than the surgeon, since each implant will be designed for a very specific and narrow purpose. "Most of these therapies can only work on one part of the complex mitral anatomy," said Howard C. Herrmann, MD, professor of medicine at the Perelman School of Medicine at the University of Pennsylvania and director of the Interventional Cardiology Program and Cardiac Catheterization Labs at the Hospital of the University of Pennsylvania. "Therefore, it's always going to be a challenge to be able to do what a surgeon, who can match different therapies to different abnormalities of the leaflet in this complex disease, can do."
Products are in development for a range of mitral valve issues, including products that target the leaflet, annulur dilation and chordae, as well as ventricular approaches and combination devices.
One investigational device is the CARILLON® Mitral Contour System™ from Cardiac Dimensions, which became available in Europe in late 2012. The stent-like implant is designed to use traction to reduce the mitral annulus dilation. The TITAN study of 65 patients found it took 6 months to 1 year for the system to achieve full improvement. A challenge with this device is the wide range of anatomic variability.
Another device on the horizon is Abbott Vascular's catheter-based MitraClip system, which enters through the femoral vein and attaches directly to the mitral valve. Trials show a better safety record transfusion and morbidity-wise, but less effectiveness than surgery. Also available in Europe, the MitraClip appeared to have a good record at preventing future surgery, as well as mortality, out to 3 years according to the registry data on mostly higher-risk patients.
"Where does that leave us? I believe MR is still mostly a surgical disease," said Dr. Herrmann. "But interventional devices will sooner or later be able to manage some of the spectrum of mitral pathology."
Oral Anticoagulants Introduce More Problems Than They Solve
Oral anticoagulants do the job they were enlisted to do—keep the clots away—making them the standard of care for US patients with AF. However, the problems with treating this growing, aging population of patients continues to include compliance, cost, and the ever-present bleeding risk. In fact, registries show that many patients aren't prescribed warfarin even when indicated by the guidelines. This is often blamed on the aforementioned challenges and on warfarin's narrow therapeutic window, which excludes a vast number of US patients. These issues don't appear to be waning.
"Coumadin (warfarin) is a pain to utilize. We need an alternative to Coumadin," said Gregory Mishkel, MD, director of the Cardiac Cath Lab at the Prairie Heart Institute in Springfield, Illinois. "Newer agents may prove to be more effective and safer, but will increase the complexity of clinical decision making and introduce new problems as they attempt to solve old ones."
Despite their novel nature, newer agents still require drug monitoring, have the risk of bleeding, and add the obstacle of not knowing if patients are above or below the therapeutic range—particularly in the 20% of AF patients who suffer from renal insufficiency.
In addition, the boxed warning on rivaroxban states that discontinuing the drug in patients with nonvavular AF increases the risk of stroke—another risk not seen with surgery.
A better strategy may be surgery to the left atrial appendage (LAA). LAA closure, unlike pharmacotherapy, is a permanent solution. As time elapses and patients move further away from the immediate post-op risks, the benefits of surgery increase, while the risks decrease.
"Device therapy is always there," said Dr. Mishkel, who counts its permanency among its benefits. This is in contrast to the transient nature of drug therapy, which patients may forget to refill, be unable to afford (a key factor since on-patent agents cost several times that of generic warfarin), develop a contraindication to, or simply choose to stop. "When you stop an anticoagulant, the patient is not protected," he added.
TAVI: The Wave of the Future or Time for a Deep Breath?
Some believe transcatheter aortic valve implantation (TAVI) may make aortic valve surgery a thing of the past. Not so fast! Extremely high costs coupled with lack of data on long-term durability makes surgery more attractive in most scenarios, said Harold L. Lazar, MD, professor of cardiothoracic surgery at Boston Medical Center, Boston University School of Medicine.
In Cohort B of the Partner Trial, the cumulative 1-year costs for TAVI were double that of medical management. In that same cohort, patients lived a little longer, but ongoing care cost triple that of medical management. Cohort A of the same trial found at 1 year, TAVI and surgery cost the same. An increase in strokes seen in TAVI patients, regardless of approach and despite being on DAPT, is also a cause for concern. Then there are what Dr. Lazar calls "hidden TAVI costs:" the requisite screening, imaging, and consultations. To make TAVI a cost-effective option, the cost of the TAVI prosthesis must decrease while durability increases.
With TAVI's limitations, it would only be indicated for a small minority of the patients for whom Dr. Lazar performed aortic valve replacements in the past 2 years. But he's certain that there will be a role for TAVI in the future. These instances he outlined include: porcelain aorta; prior chest wall irradiation with ≤19 mm annulus; cirrhosis greater than Class A; previous cerebrovascular accident with significant residual dysfunction; end-stage lung disease on steroids; and as a bridge to surgical aortic valve replacement in place of balloon valvuloplasty in patients with refractory pulmonary edema or cardiogenic shock to improve their hemodynamic state and reduce surgical risks. However, he said, surgery remains the best bet. "In the long-run, TAVI will be inferior to surgery."
Left Main PCI Will Make CABG Obsolete!
PCI, the less-invasive distant cousin to CABG, appears to be making a run at tackling left main disease. In certain instances PCI may be preferable to CABG. However, it's not yet time to write CABG's eulogy. In fact, in more complex and severe cases—advantage: CABG.
CABG gets the nod, according to Sheldon Goldberg, MD, professor of medicine at Drexel University College of Medicine, for several reasons, including:
- CABG, hands down, allows for more complete revascularization.
- When CAD is severe, CABG piles on little increased risks.
- By contrast, with complex disease—which is most often the case—PCI boosts risks with each added stent. (In fact, in 80% of cases there are lesions in other vessels beyond left main disease.)
- The survival benefit of CABG is most dramatic with increased CAD. With stents, not so much.
- CABG is also superior if there are lesions in other vessels—which is the case four out of five times.
For left main disease, PCI may sound more pleasing to patients, who understandably may balk at the thought of open heart surgery. However, there are several issues with PCI in left main disease, said Dr. Goldberg. He poses the following questions that must be answered before CABG can be definitively deemed obsolete in favor of PCI:
- Is the left main lesion truly significant? (Unfortunately, this, the most dangerous location, also has the most interobserver variability.)
- Are the lesions in the other vessels clinically significant enough to justify intervention along with the associated increased risk?
- Are there other, special considerations such as the location of the lesion, degree of calcification, LV function, and peripheral arterial disease that will influence how the procedure is done?
On the flip side, newer appears to mean better when it comes to the latest generation of stents, which have lower stent thrombosis rates. "Advances in stent technology will improve long-term results," said Dr. Goldberg. "Participation in clinical trials like EXCEL will refine revascularization strategies and techniques."
With technological advances in the stents themselves, along with better characterization of lesions via fractional flow reserve (FFR) and IVUS (as opposed to angiography alone)—PCI will likely gain on CABG's lead.
"In the future," Dr. Goldberg said, "in selected patients, PCI will prevail." The future, however, hasn't arrived yet.
Platelet Function Testing: Get Your Heads Out of the Sand!
Despite some reluctance, evidence points to a day when platelet function testing (PFT) prior to PCI will be far more common, so you might as well accept it.
PFT serves as both a camera and a crystal ball, providing a snapshot of the present as well as a sneak peek into the future. Diagnostically, it reports current evidence of a P2Y12 antagonist effect once the antiplatelet drug is administered. Prognostically, it assesses and quantifies the risk of future CV events in the patient based on the level of platelet activity. Patients who show no effect have worse outcomes; those who do show an effect have better outcomes.
Both features make PFT a valuable tool, which could alter the approach and improve safety among patients undergoing PCI, said Matthew J. Price, MD, of Scripps Health and Scripps Translational Science Institute in La Jolla, California.
Dr. Price points to several trials that support this, including a post-hoc analysis of his GRAVITAS study. The analysis found that after adjusting for standard risk factors for recurring events after PCI, patients with a platelet reactivity unit (PRU) <208 had significantly lower rate of CV events. Similar results came from the ADAPT-DES trial of more than 8,000 patients. Those subjects with a PRU of >208 had an adjusted hazard ratio of more than triple that of patients with lower PRU. "There is no incremental benefit of having a higher level of active metabolite," he said. "You only get more bleeding.
"The reason we give clopidogrel is to block the P2Y12 receptor, which we know reduces events," said Dr. Price. The value of PFT goes beyond clopidogrel and extends to the latest generation of agents. "The absolute benefit of one of the newer agents will be less in patients with a detectable clopidogrel effect, a waste of money, and probably a waste of blood transfusions. PFT can therefore identify patients in whom the costly, newer agents will likely provide the greatest benefit."
Side note: Newer DES appear to pose fewer threats since they have lower event rates. Patients undergoing elective PCI with newer-generation DES appear to have low event rates regardless of platelet function.
Should FFR Imaging Overrule Clinical Judgment in "Stable" CAD Patients?
According to sci-fi novels, in 2013, we should now commute via hovercraft and communicate telepathically, so the notion of allowing FFR to replace expert judgment seems almost… logical. There's only one problem—well, actually, there are several, according to Jeffrey W. Moses, MD, professor of medicine at Columbia University Medical Center in New York.
First, when relying on FFR, there are limitations that impede the ability to have maximum flow, as there could be branches between serial stenosis that may inhibit maximal hyperemic flow. Also, left ventricular hypertrophy (LVH) can cause inadequate flow reserve because of a mismatch between the vasculature and myocardial mass. Then there is exercise-induced vasoconstriction, which isn't accounted for with FFR, but can also impact angina.
"In the face of microvascular damage in the case of MI, less achievable flow reserve can actually make a specific region, in a viable region, look negative in FFR," Dr. Moses said. Additionally, there is variation in the metabolism of adenosine, whether administered systemically or locally. "It also gets very complicated in tandem lesions."
Another drawback: the validation for FFR was stress testing in some studies and MPI in others. That makes it counterintuitive for FFR to override demonstrable ischemia.
If patients have symptoms, clinical judgment must reign supreme. In other words, FFR numbers can't be taken as gospel. "It needs to be put in the context of our overall understanding of coronary physiology, the prognosis of CAD and the influence of revascularization in various clinical and anatomic situations."
Now, this isn't about bashing FFR, which Dr. Moses said he "loves" in part because of its role in dismissing the notion of so-called stable angina. "This is not a stable condition," he said.
FFR should be considered one of many tools in the tool bag, with clinical judgment at the helm.
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