John Mandrola, MD


March 05, 2018

The American College of Cardiology (ACC) Scientific Sessions in Orlando, Florida, begins with a bang.

Professor P. Gabriel Steg (Bichet Hospital, Paris, France), will present results of the ODYSSEY-CV Outcomes trial,[1] a randomized controlled trial testing the PCSK9 inhibitor alirocumab against placebo in patients with recent acute coronary syndrome.

Last year's ACC presentation of the FOURIER trial showed that the PCSK9 inhibitor evolocumab reduced nonfatal cardiac events without changing overall death rates.[2] Despite dramatic low-density lipoprotein cholesterol (LDL-C)–lowering effects and positive results in a large trial, PCSK9 inhibitors have not enjoyed market success in the United States. Reasons include high costs, barriers set up by third-party payers, or, perhaps, that clinicians remain unconvinced by the drugs' modest effects on outcomes.

This is why ODYSSEY's results are important. If alirocumab shows a similar small reduction in cardiac events without lowering death rates, PCSK9 inhibitors will have to be priced far lower to survive. On the other hand, if ODYSSEY delivers robust reduction in cardiac events and lower death rates, PCSK9 inhibitors could become blockbuster drugs.

There are important differences between the two trials. ODYSSEY has a longer follow-up than FOURIER, which matters because LDL-C reduction takes time to reduce events. ODYSSEY's protocol calls for titrating to an LDL-C of less than 50 mg/dL, and this will likely result in lower average LDL-C levels than in FOURIER.  These two factors favor more robust outcomes from ODYSSEY. But the primary composite endpoint in ODYSSEY is death, myocardial infarction (MI), stroke, or hospitalization for unstable angina — arguably a higher hurdle to clear than in FOURIER, which included the "soft" endpoint of coronary revascularization.

Wearable Cardiac Defibrillator

The VEST trial explores the hypothesis that wearable defibrillators can decrease mortality by reducing sudden death in the immediate post-MI period. The primary outcome is sudden death; overall mortality is a secondary outcome.

This is an important trial because the evidence supporting wearable defibrillators comes from industry-sponsored registries, observational data, and anecdotes. Two previous randomized trials testing internal defibrillators in the immediate post-MI period failed to show a mortality advantage.[3,4]

Mobile Health Screening

On paper, the mobile Health Screening to Prevent Strokes (mSToPS) study looks to be an example of "smart" screening — "smart" because this study screens for atrial fibrillation (AF) only in people who might benefit from intervention.

Investigators from Scripps first used claims data to identify a high-risk group of patients. Half will undergo an immediate monitoring strategy with the Band-Aid–like Zio XT patch monitor (iRhythm Technologies Inc), and the others will receive usual care for 4 months and then delayed monitoring with the patch. Incidence of new AF at the end of the monitoring period is the primary outcome. Time to first embolic event and total healthcare costs are key secondary measures. A subset of patients in both groups will wear an additional wrist monitoring device.

A scan of the ACC program shows numerous papers on detection of AF with personal devices, such as smartphones and watches. Doctor-controlled implantable loop recorders now have the edge, but soon, patient-controlled personal devices will catch up. This will be a fun space to watch over the next few years.

Personalized Medicine on Trial

Both the ADAPT and PHARMCLO trials will use different point-of-care tests to compare genotype-guided antiplatelet therapy in patients undergoing PCI.

Clopidogrel is a prodrug requiring conversion to an active drug by the liver enzyme CYP2C19. Gene variants in this enzyme are common and may lead to graded degrees of loss-of-function (inadequate metabolism of clopidogrel) as well as gain-of-function (increased metabolism) alleles, resulting in reduced platelet inhibition or increased bleeding, respectively.

A meta-analysis of nine studies found that having even one loss-of-function CYP2C19 allele was associated with an increased risk for cardiac events.[5] In 2010, the FDA issued a boxed warning on the reduced effectiveness of clopidogrel in patients who are poor metabolizers. Neither prasugrel nor ticagrelor metabolism has been associated with clinical outcomes.

It makes sense that knowing a patient's response to clopidogrel and then tailoring antiplatelet drugs would improve outcomes. But nearly a decade ago, three clinical trials using this personalized approach failed to show benefit.[6,7,8] These studies tested platelet reactivity — phenotype — rather than genotype. I would think phenotype would be a better tool because genetic variations in CYP2C19 explain only 11% of the antiplatelet response.[9]

Easy-to-use point-of-care genotype assays for CYP2C19 have recently become available. This year, a nonrandomized multicenter pragmatic trial using genotype-guided antiplatelet therapy found a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele when clopidogrel rather than alternatives (prasugrel/ticagrelor) was prescribed.[10]

If ADAPT and PHARMCLO show the same benefit, we may see more use of these assays.

His-Bundle Pacing Is Not Just for EP Nerds

The title of this next presentation gives away the results (emphasis mine): "Permanent His Bundle Pacing (HBP) Is Associated with Reduction in Mortality and Morbidity Compared to Right Ventricular Pacing: Results From the Geisinger His Bundle Pacing Registry."

Pacing the right ventricle (RV) involves tradeoffs. When you pace the RV, you create a dyssynchronous contraction, which, of course, is better than no contraction. But in 2018, operators willing to learn a new technique and to spend a few extra minutes during the implant, can — in most cases — place the ventricular lead in the region of the his-bundle. This allows for simultaneous activation of the heart and an impressively narrow QRS.

Preliminary studies have shown that HBP pacing preserves left ventricular (LV) systolic function,[11,12] is associated with lower rates of heart failure hospitalization,[13] and may be a feasible alterative to cardiac resynchronization therapy with an LV lead compared with standard RV pacing.[14,15] Downsides of his-bundle pacing, such as higher rates of lead revisions, and higher pacing thresholds highlight the need for randomized clinical trials.

HBP is not an esoteric electrophysiology topic. Patients and doctors alike should know that this technique reduces or eliminates one of the greatest downsides of a pacemaker: overt heart failure from dyssynchronous RV pacing.[16,17]  I predict that some day soon we will shun standard RV pacing in the same we shun femoral artery access for coronary angiography.

Hope for Patients With HFpEF? 

Despite dazzling advances in cardiology in the past couple of decades, patients who have heart failure with a preserved ejection fraction (HFpEF) have few options. These patients experience dyspnea on exertion and impaired exercise tolerance, and nothing seems to work for them.

Could the INDIE-HFpEF Trial[18] buck this trend? The intervention is an inhaled sodium inorganic nitrate given three times daily. The investigators chose peak VO2 as the primary outcome, along with a slew of other secondary outcomes. It would be cool if a puffer helped these patients feel better.

Blood Pressure in Black Barbershops

Numerous studies report racial disparities in access to healthcare and outcomes.[19,20] Black patients are especially vulnerable to high blood pressure.[21]

In Barber-1, a cluster randomized trial among 17 black-owned barbershops in Dallas County, Texas, blood  pressure control among black male barbershop patrons improved when barbers were enabled to become health educators, monitor blood pressure, and promote physician referral.[22]

Investigators from this novel study will present further results during a late-breaking clinical trial session on March 12. I love this idea because I think public health turns not on the medical profession but on society itself. 

Safety of Gout Drug Febuxostat

Something is up with the gout drug febuxostat. In November 2017, the US Food and Drug Administration (FDA) alerted the public to preliminary results of the cardiovascular safety trial called CARES[23] — a large noninferiority trial pitting febuxostat against allopurinol.

Specifically, the FDA reported that while no differences were seen in the overall composite endpoint, febuxostat showed an increased risk for heart-related deaths and death from all causes.

The FDA required the new gout drug to pass a cardiovascular safety trial (similar to what it requires for diabetes drugs) because the clinical trials conducted before approval showed a higher rate of heart-related problems in patients treated with febuxostat compared with allopurinol.

Like allopurinol, febuxostat lowers levels of uric acid; high levels of uric acid are also associated with an increased risk for cardiac events [24,25] At ACC, we will learn details of the trial, and the results could alter treatment of patients with gout.

PFO Closure for Cryptogenic Stroke

In 2017, the New England Journal of Medicine published three large randomized controlled trials of patent foramen ovale (PFO) closure for secondary prevention after cryptogenic stroke.[26,27,28] Notwithstanding caveats, all three produced positive results compared with medical therapy.

South Korean investigators will report results of DEFENSE-PFO, a smaller (approximately 200 patients) PFO closure vs medical therapy study. The trial's registration suggests patients in the medical group will be receiving both anticoagulants and antiplatelets. The ratio is key because one of the criticisms of previous trials is that PFO occlusion may have been superior to aspirin, but anticoagulants are the more appropriate comparator.

Factor Xa–Reversal Agent

When offered anticoagulant therapy with factor Xa inhibitors, many patients ask about reversal agents. To date, there isn't one available.  In 2016, ANNEXA-4 investigators published interim results of a reversal agent in 67 patients. Andexanet alfa substantially reversed anti–factor Xa activity in patients with major bleeding who were receiving rivaroxaban and apixaban.[29]

At the time, however, Portola Pharmaceuticals  announced that the FDA had asked the company for additional information on manufacturing the drug before its potential approval.

At ACC, we will hear an interim report on the ANNEXA-4 study: "Andexanet for Reversal of Anticoagulation in Factor Xa - Associated Acute Major Bleeding." It would be nice to be able to reassure patients that an antidote is coming soon.

Clinician Wellness

In a press briefing, ACC president Dr Mary Norine Walsh mentioned that this year's meeting will focus on clinician wellness. I support cardiology's embrace of the quadruple aim,[30] which adds the goal of improving the work life of clinicians and staff to the IHI triple aim. The worst part of our current crisis of joylessness and burnout is that it too often afflicts our young people.

If you want to hear more about the upcoming ACC meeting, check out the latest Heart podcast from the BMJ, where I was a guest of host Dr James Rudd.

And as always, | Medscape Cardiology team will work hard to deliver the best coverage. Stay tuned.

Follow us on  Twitter and  Facebook . Meeting hashtag: #ACC18


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