ACCEL: American College of Cardiology Extended Learning

Is It Time to Rethink AF Therapy with Patients?
How to apply the AF guidelines in clinical practice

Treatment of atrial fibrillation (AF) involves three major strategies: prevention of stroke, maintenance of sinus rhythm, and rate control. Stroke is the most dreaded complication of AF, and its prevention is key.

Eric N. Prystowsky, MD, FACC, is a pioneer in electrophysiology and the cardiovascular disease program director at St. Vincent Hospital in Indianapolis, IN. He was involved in the development of the first two sets of AHA/ACC guidelines for managing patients with AF,1 but rotated off the guidelines committee for the most recent set.2

“We’re getting more and more choices to manage AF,” he said. Some of the new guideline recommendations are confirming what we knew in the past, he added, while others underscore “twists and turns.”

For example, we’re back to a controversy that some people thought ended years ago in terms of which is better: a rate or a rhythm control strategy. The issue seemed to be settled by the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) study, which suggested rhythm-control offers no survival advantage over rate-control strategy, plus there may be a lower risk of adverse drug effects with a rate-control strategy.3

However, Dr. Prystowsky noted the mean age of study participants was almost 70 (mean: 69.7 years) and mean follow-up was 3.5 years. AFFIRM shows documented safety of persistent AF in a small slice of the population, roughly age 62 to 72. Moreover, more recent data suggests that patients treated with rhythm control had reduced mortality when follow-up was extended beyond 4 years.4

There are really no safety data, he said, regarding allowing patients to stay in AF for 20, 30, or 40 years. Given evidence of potential deleterious effects of longstanding AF, such as cognitive effects, dementia, and even Alzheimer’s (with the greatest risk in those < 70 years of age), Dr. Prystowsky said. “I am not telling you what to do. What I am asking people to do is to rethink this issue with your patients. There are new data suggesting that leaving patients in AF is not as safe as you think.”

One change in the current guidelines: radiofrequency catheter ablation may be considered as first-line therapy in select patients before a trial of antiarrhythmic drug therapy when a rhythm-control strategy is desired. The recommendation applies to ablation done in experienced centers. That’s important, according to Dr. Prystowsky: “There was a paper published a couple years ago which was frankly appalling to me, that suggests the vast majority of AF ablations done in this country are being done by those who do fewer than 25 a year.” While it’s a personal opinion and not a guideline, he added, “If that’s all you’re doing in a year, perhaps you should rethink whether you should be doing them.”

In terms of rate control, one change Dr. Prystowsky wholly supports relates to tight rate control. In between the previous guidelines and the new set, there was an interim update that gave strict rate control a class III recommendation, meaning don’t do it. “Many of us felt that was inappropriate and I am really pleased that the latest guideline committee took that (issue) up.” A class IIa recommendation is now given to heart rate control (resting heart rate < 80 bpm) as a reasonable strategy for symptomatic management of AF. And lenient rate control (resting heart rate < 110 bpm) dropped down to a class IIb recommendation.

Preserve the Brain

According to Dr. Prystowsky, the “prime directive of AF management” is to preserve the brain. He has written about this in JACC,5 emphasizing that stroke is not the only neurological consequence of AF. Cognitive impairment and silent cerebral infarcts (SCIs) without clinical strokes have been reported in patients with AF. “This is a passion of mine,” he said, “and I think it is, unfortunately, not something we always think about as much as we should.”

One way to lower stroke risk and better protect the brain: assess risk using the broader CHA2DS2-VASc risk assessment tool (class I recommendation). With prior stroke, TIA, or a CHA2DS2-VASc score > 2, oral anticoagulants are recommended (class I recommendation) based on shared decision-making, with a discussion of the risk of stroke and bleeding and patient preferences (also a class I recommendation). “In my own experience,” he said, “it takes about 10 minutes to go over this with my patients. It’s a very important decision that is well worth the time and then you make a shared decision.”

In terms of choice of anticoagulant therapy, warfarin versus a novel oral anticoagulant (NOAC), Dr. Prystowsky offered his own approach:

  • Have an in-depth discussion with the patient concerning the risks/benefits of various anticoagulant therapies.
  • For the patient who is taking warfarin and has had stable time in therapeutic range and prefers not to change: leave well enough alone.
  • For patients just starting anticoagulation who have no reason to avoid a NOAC: prescribe a NOAC.

“Personally, I don’t think you should push either agenda,” he added. “Both are class I recommendations and I think it is up to you and the patient.”


Bridging is always an important issue, and as Dr. Prystowsky knows from having defended physicians, this is not an uncommon medico-legal issue. He said he was pleased to see the guideline directives are clear (all class I; level of evidence C):

  • Bridging therapy with LMWH or unfractionated heparin is recommended with a mechanical heart valve if warfarin is interrupted. Bridging therapy should balance risks of stroke and bleeding.
  • Without a mechanical heart valve, bridging therapy decisions should balance stroke and bleeding risks against the duration of time patient will not be anticoagulated.
  • For atrial flutter, antithrombotic therapy is recommended as for AF.

“If you have a mechanical heart valve, bridging is important,” he said, “but honestly anything other than that it is you decision with the patient based on risks and benefits.”

It is a little different, he said, when the issue is cardioversion. In the setting of AF or atrial flutter (they are treated the same for cardioversion), the guidelines recommend (all class I):

  • With AF or atrial flutter for > 48 hours, or unknown duration, anticoagulate with warfarin for at least 3 weeks prior to and 4 weeks after cardioversion.
  • With AF or atrial flutter for > 48 hours or unknown duration requiring immediate cardioversion, anticoagulate as soon as possible and continue for at least 4 weeks.
  • With AF or atrial flutter for < 48 hours and high stroke risk, IV heparin or LMWH or factor Xa or direct thrombin inhibitor is recommended before or immediately after cardioversion, followed by long-term anticoagulation.
  • Following cardioversion of AF, long-term anticoagulation should be based on thromboembolic risk.

The third bullet point is new. It’s given a level of evidence C, meaning expert opinion, but Dr. Prystowsky asked what if the patient has had AF or atrial flutter less than 4 hours: do you still need to anticoagulate first? In the past, he said, many clinicians would have said no to this. “It becomes a problem for clinicians and, I hate to say it, it become a medico-legal problem, too,” he said. “I could understand if they said greater than 24 but less than 48 hours, but I don’t know of any data to suggest that if a patient has had AF for 4 hours, you’re putting someone at high risk of you don’t anticoagulated them first.”

Considering the new guidelines, Dr. Prystowsky said the committee did a wonderful job of getting everyone up-to-date. “Clearly, in the anticoagulation area there are changes and they are going to affect clinical practice.”

He added, “I say this as a person who spent years writing guidelines: they are guidelines—not the tablets from the mountain. As a clinician, and it is stated in the (guidelines) preface, you need to incorporate them into patient care the best way you can.”


  1. Anderson JL, Halperin JL, Albert NM, et al.
  2. J Am Coll Cardiol. 2013;61(18):1935-44.
  3. January CT, Wann L, Alpert JS, et al. J Am Coll Cardiol. 2014;64:e1-e76.
  4. Wyse DG, Waldo AL, DiMarco JP, et al.
  5. N Engl J Med. 2002;347:1825-33.
  6. Ionescu-Ittu R, Abrahamowicz M, Jackevicius CA, et al. Arch Intern Med. 2012;172:997-1004.
  7. Prystowsky EN, Padanilam BJ. J Am Coll Cardiol. 2013;62:540-2.

PCSK9: New Kid in Town
FDA approval now puts reimbursement in the spotlight

There is a new option for patients at high risk from high cholesterol. What we don’t know, yet, is whether these new drugs (another is in the wings) represent a true breakthrough—or whether we can even afford them.

On July 21, 2015, the European Commission approved Amgen’s PCSK9 inhibitor, evolocumab, for the treatment of patients with uncontrolled cholesterol who require additional intensive LDL-C reduction. That makes Repatha (as it’s called) the first PCSK9 inhibitor to be approved by any regulatory agency in the world. A few days later, alirocumab (Praluent), from Regeneron Pharmaceuticals Inc. and Sanofi SA, was approved by the U.S. Food and Drug Administration. (The FDA press release is here:

The FDA approved alirocumab for use in addition to diet and maximally-tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia or patients with clinical atherosclerotic cardiovascular disease such as heart attacks or strokes, who require additional lowering of LDL cholesterol.

A little more than a month later, as this issue of CardioSource WorldNews was being finalized, the FDA agreed with their European counterparts: evolocumab injection was approved as an adjunct to diet and maximally-tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C; and as an adjunct to diet and other LDL-lowering therapies for the treatment of patients with homozygous familial hypercholesterolemia, who require additional lowering of LDL-C. (The FDA evolocumab press release is here: )

If you want an update of this new class of drugs, check the July 23, 2015, issue of JACC; Robert P. Giugliano, MD, FACC, and Marc S. Sabatine, MD, MPH, FACC, (both of Boston’s Brigham and Women’s Hospital), published a state-of-the-art review of these new drugs.1 They note that they evolved from the first identification of PCSK9 in 2001 to a series of discoveries that gain-of-function mutations in PCSK9 could cause hypercholesterolemia, while loss-of-function mutations in PCSK9 reduced cholesterol. In the latter case, the modest (15% to 28%), but lifelong, lowering of LDL-C appeared to confer considerable protection from the development of coronary heart disease (CHD).

Thus, the stage was set for the development of therapies that could inhibit PCSK9, lower LDL-C, and, hopefully, reduce atherothrombotic events. The new drugs mediate degradation of LDL-C receptors. By increasing the numbers of LDL receptors, PCSK9 inhibitors essentially work by escorting the LDL receptors to their demise.

Sticker Shock

Since these drugs are monoclonal antibodies (MoAbs), which are expensive to produce, they are expected to be priced accordingly: up to $12,000 a year, according to a recent estimate from CVS Health, one of the nation’s largest pharmacy benefit managers. Turns out, that estimate was a little low: alirocumab (Praluent) and the aforementioned evolocumab. A decision on evolocumab is due by August 27, while a decision on alirocumab was launched with a list price of $40 a day, or $14,560 a year. Compare that to many statins, which are available as generics costing just a few dollars a month.

Due to the price tag, reimbursement will likely limit the drug to high-risk patients, despite statin therapy, or those individuals who truly (truly!) cannot take statins. That bar will likely be high given that many patients who have some difficulty taking a statin often find effective statin therapy after trying different drugs or different drug dosages.

The top doses being developed of alirocumab (150 mg subcutaneously [SC] every 2 weeks) and evolocumab (140 mg SC every 2 weeks or 420 mg SC every 4 weeks) administered for a total of 12 weeks have been shown to reduce LDL-C by 60% to 70%. (See the Table for a summary of phase III trial data.) While these drugs drive down levels of LDL-C to ranges not possible with existing therapies, the problem is they haven’t been studied long enough to know whether they actually prevent heart attacks and strokes; in other words, we don’t know yet whether they save lives.

Both alirocumab and evolocumab significantly reduce apolipoprotein B, too, as well as total cholesterol, triglycerides, and non–high-density lipoprotein cholesterol (HDL-C). As would be expected, given their mechanism of action, these drugs only minimally (if at all) increase lipoprotein(a), HDL-C, and apolipoprotein A.

What about getting some outcomes data? There are four ongoing large, placebo-controlled phase III trials in >70,000 patients investigating whether PCSK9 inhibitors on a background of statin reduce cardiovascular (CV) events. Completion of these trials is projected for late 2017. In the interim, the FDA is making its decisions on the basis of phase II and III studies completed through mid-2014.

The safety and tolerability profile of the two most extensively studied MoAbs (alirocumab, evolocumab) for periods of up to 2 years appears promising; however, longer exposure is necessary to more completely evaluate potentially delayed adverse effects, such as neurocognitive impairment or cancer. Given the reduction in LDL-C observed in phase II and III trials to date and the analyses of CV events in longer-term studies, major vascular events could be reduced by 40% to 50% in high-risk patients if the benefits follow a similar relationship as that observed with statins.

Overall, the authors of the JACC review caution against excessive exuberance pending the results of the ongoing CV outcome trials. Furthermore, given increasing constraints on health care spending and the higher bars being set by the Centers for Medicare and Medicaid Services for coverage determination of novel therapies, Giugliano and Sabatine anticipated the availability of MoAbs to PCSK9 will be limited initially to those patients who are at high cardiovascular risk, who have an LDL-C that is not well controlled despite intensive therapy with a statin + ezetimibe, or who cannot tolerate statin therapy.

(Editor’s Note: ACCEL has featured several interviews discussing these drugs, including Patrick M. Moriarty, MD, FACC, [September 2015], Jennifer Robinson, MD [May 2015], and Erik S.G. Stroes, MD [October 2014].)


  1. Giugliano RP, Sabatine MS. J Am Coll Cardiol. 2015;65:2638-51.

Running for Your Life
Even at ‘low doses,’ running offers substantial mortality benefits

It is the Second Running Boom and still going strong as it enters its third decade. Overall, according to the latest available data from Running USA, there were 19,025,000 finishers in U.S. running events in 2013 (a record).1 Females represented the highest percentage ever reported (57%) but both males and females set new record high participation rates.

Those numbers, however, pale compared to leisure runners. While you might think of jogging as an activity consistently popular with a proportion of the populace, the number of self-reported joggers/runners in the U.S. has increased from 45.67 million in the spring of 2008 to 65.48 million in the spring of 2014, a 43.4% increase.

Clearly, running is a popular leisure-time physical activity, but what do we know about the long-term effects of running on mortality? Similarly, is there a dose-response relationship between running and mortality?

Running and Mortality

The Aerobics Center Longitudinal Study is a prospective, observational cohort study designed to examine the effects of physical activity and fitness on various health outcomes. Conducted by the Cooper Clinic in Dallas, TX, investigators recently reported the association of running with all-cause and CV mortality risk in 55,137 adults, 18 to 100 years of age (mean age 44 years), 24% of whom participated in regular running/jogging.2

During a mean follow-up of 15 years, 3,413 all-cause and 1,217 CV deaths occurred. Compared with nonrunners, runners had 30% and 45% lower risks of all-cause and CVD mortality, respectively, after adjusting for potential confounders. These associations were consistent regardless of sex, age, BMI, health conditions, smoking status, and alcohol consumption.

Dr. Lavie and colleagues noted that not running was almost as negative an influence as other prognostic variables such as smoking, obesity, or hypertension (TABLE). Also, nonrunners had a lower life expectancy of 3 years compared with runners after adjusting for other mortality predictors.

Investigators analyzed intensity of running/jogging activity by assessing quintiles of running time, distance, frequency, amount, and speed compared with nonrunners. Even participation at the low end of these ranges—weekly running < 51 minutes, < 6 miles, 1 to 2 times, < 506 metabolic equivalent-minutes, or < 6 miles/hour—was sufficient to reduce risk of mortality, compared with not running.

However, mortality benefits were similar between lower and higher doses of weekly running time. In fact, among runners (after nonrunners were excluded in the analyses), there were no significant differences in HRs of all-cause and CVD mortality across quintiles of weekly running time (all p values > 0.10).

Running, More or Less

Recently, the Copenhagen City Heart Study found similar mortality benefits in 1,878 joggers compared with nonjoggers,3 after adjusting for a similar set of confounders as that used by the Aerobics Center Longitudinal Study. The Denmark team also reported that jogging even < 1 hour per week or only one time per week was associated with significant mortality risk reduction compared with sedentary non-joggers.

However, in a dose-response analysis, the Copenhagen authors observed a U-shaped relation between jogging time and mortality. Compared with no jogging, weekly jogging < 150 minutes was associated with mortality reduction; however, > 150 minutes of weekly jogging did not show significant mortality benefits. This finding could have been due to the small numbers of deaths and wide confidence intervals in that category. The most favorable results for reducing mortality were seen for 1 to 2.4 hours of jogging per week, with a frequency of 2 to 3 times per week, at a slow or average pace.

On the other hand, the Cooper Clinic study of more than 13,000 runners used quintiles of weekly running time to have an equal number of participants across different doses of running. Dr. Lavie and colleagues found a lower mortality risk in running > 150 min/week. However, mortality benefits were slightly less at the highest quintile of weekly running time of > 176 min/week.

When the Copenhagen City Heart Study was published, Dr. Lavie (along with Duck-chul Lee, PhD, and Rajesh Vedanthan, MD, MPH) wrote in an accompanying editorial comment that the evidence suggests that < 1 hour of jogging per week—below the current minimum guidelines of vigorous-intensity aerobic physical activity of > 75 minutes per week—may be sufficient for mortality benefits.4 This is consistent with other large studies (including the new study from Dr. Lavie and others). Therefore, as a better option for time efficiency, they wrote, “We should emphasize that even small amounts of running (< 1 h per week) can provide significant mortality benefits for most healthy but sedentary people.”

In a commentary accompanying the publishing of the Aerobics Center Longitudinal Study, the authors noted that this was good news for the sedentary.5 They pointed out that the minimal amount of jogging shown to be beneficial by Dr. Lavie and colleagues was similar to the 15 min/day of brisk walking reported in the Lancet in 2011 by Wen et al.6 “Both showed a 3-year extension of life expectancy, and both are good news to the sedentary because finding 5 to 15 min per day to exercise is much easier than finding 30 min.” They also noted that prior to the studies by Drs. Lavie and Wen, no conclusive timeline had been identified with sufficient statistical power to show definitive health benefits.

Dr. Lavie and his coauthors noted in their paper that health care providers should explain to patients the significant mortality benefits of running even as little as 5 to 10 minutes daily; even 5 to 10 minutes of walking per day was associated with a mortality benefit. They wrote: “Try to motivate patients to start running and to continue running as an attainable health goal.”


  1. [No authors listed] Running USA. 2014 State of the Sport - Part III: U.S. Race Trends. Last accessed July 5, 2015.
  2. Lee DC, Pate RR, Lavie CJ, et al. J Am Coll Cardiol. 2014;64:472-81.
  3. Schnohr P, O’Keefe JH, Marott JL, et al. J Am Coll Cardiol. 2015;65:411-9.
  4. Wen C, Wai J, Tsai M, Chen C. J Am Coll Cardiol. 2014;64:482-4.
  5. Lee DC, Lavie CJ, Vedanthan R. J Am Coll Cardiol. 2015;65:420-2.
  6. Wen CP, Wai JP, Tsai MK, et al. Lancet. 2011;378:1244-53.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Sports and Exercise Cardiology, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Nonstatins, Exercise

Keywords: CardioSource WorldNews, Atrial Fibrillation, Cardiovascular Diseases, Cholesterol, Electrophysiology, Jogging, Leisure Activities, Running, Stroke, United States Food and Drug Administration

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