Cardiology's Top 10 Stories of 2014: Back-to-Basics Promises Big Advancements

John M. Mandrola, MD


December 11, 2014

There were many great stories in cardiology this year. Some of the most useful ones stemmed from negative findings. That's OK; finding out what doesn't work is helpful. Other choices are less about specific trials and more about changes in ways of thinking. Here's my list.

1. The Failure of Renal Denervation

Few negative trials teach us as much as the sham-controlled, prospective, single-blinded, randomized clinical trial of renal denervation called SYMPLICITY-HTN-3.[1]

Before 2014, the excitement at medical meetings surrounding kidney ablation was striking. The unblinded trials that preceded SYMPLICITY HTN-3 declared dramatic blood pressure reductions. Millions of patients have hypertension and millions suffer from its complications. Renal denervation promised an easy solution: We could thread a catheter up to the kidneys, deliver radiofrequency energy, not measure an ablation effect, and voilà—hypertension would be vanquished. Proceduralists and medical device companies were tingling with anticipation.

Then reality hit. The nonsignificant blood pressure reductions in the properly controlled SYMPLICITY HTN-3 trial confirmed the old adage: If something looks unbelievable, it probably is. Other lessons included the power of hype, the misthink of treating systemic lifestyle diseases with focal solutions, the temptation of intervention bias, and the importance of basing clinical practice on sound science.

Dr Anthony DeMaria was the editor of the Journal of the American College of Cardiology (JACC) at the time. His introspection on renal denervation is notable.[2]

As JACC editors, we tend to place a very high importance on novelty in deciding whether to accept or reject a submitted manuscript... these considerations may help to explain how studies that have relatively small sample sizes, no or limited controls, and less than absolutely perfect methodology achieve such prominence in the medical literature.

It's worth closing this topic on a positive note. It would be incurious to consider renal denervation a hopeless strategy. It was never going to be an antidote for eating too much and moving too little, but one can see its potential value in small cohorts of patients with diseases of catecholamine excess, such as ventricular tachycardia storm.[3]

2. ARNI: A New Class of Drug for Congestive Heart Failure

The impressive results of the PARADIGM-HF trial may be the first breakthrough in drug therapy for heart failure in more than two decades.[4]

Investigators compared the novel combination drug LCZ696 (valsartan/sacubitril; Novartis still has not given it a brand name) with standard-dose enalapril in a multicenter clinical trial. The idea behind angiotensin-neprilysin inhibition (ARNI) drugs is that the addition of the neprilysin inhibitor (sacubitril) to the angiotensin-receptor blocker (ARB) will help counter the unfavorable vasoconstriction, sodium retention, and negative remodeling seen with neurohormonal activation in heart failure patients.

The results of PARADIGM-HF were clear. LCZ696 lowered the rate of the primary endpoint, a composite of cardiovascular (CV) death or first hospital admission for heart failure, by 4.7%. The novel drug also lowered the most important endpoint, premature death from any cause, by 2.8%. Functional status and quality-of-life measures favored LCZ696. Renal function remained stable with the study drug.

But there are still reasons for concern. One problem with LCZ696 may be its more potent blood pressure–lowering effect. The run-in phase before the trial excluded approximately 12% of patients because of adverse effects (mostly hypotension). There are no run-in phases in the real world. Another criticism of PARADIGM-HF centered on the (low) dosing of the comparator agent, enalapril. Were the benefits of LCZ696 simply due to more potent afterload reduction? Finally, the drug has yet to be submitted for FDA approval, a process that often uncovers relevant details.

3. Cardiac Monitoring

This was a good year for novel cardiac monitoring technologies.

The CRYSTAL AF trial[5] showed that an implantable loop recorder (ILR) was six times more likely than conventional monitoring to detect atrial fibrillation (AF) in patients who had just suffered ischemic stroke. The majority of ILR-detected cases of AF were asymptomatic. The EMBRACE trial,[6] published alongside CRYSTAL-AF in the same issue of the New England Journal of Medicine, confirmed the value of extended monitoring after cryptogenic stroke or transient ischemic attack. In that study, Canadian researchers detected new AF in one in six patients using 30-day ambulatory ECG recorders.

These are notable studies because detecting AF may lead to beneficial changes in therapy—namely, anticoagulation.

LINQ implantable loop recorder next to the Reveal XT implantable cardiac monitoring device. Photo courtesy of John Mandrola, MD

AF monitoring really took off in 2014 when Medtronic released their newest ILR, which they call the LINQ. The generously reimbursed wireless device can be injected under the skin of an un-sedated patient in as little as 90 seconds. Enthusiasm among cardiologists is high. And, on paper, these devices hold promise for improving outcomes in patients at risk for stroke. The problem is that truly helping patients is not about implanting the device but about the labor-intense process of data interpretation. Whether we are up to being good stewards of this new technology remains to be seen.

Patients with AF and stroke weren't the only beneficiaries of new monitoring capabilities. Patients with pacemakers and ICDs also benefited from remote wireless monitoring technology built into their devices. Four studies[7,8,9,10] presented at the Heart Rhythm Society Scientific Sessions confirmed that patients with cardiac devices enrolled in remote monitoring programs are less likely to die during follow-up. Although these were not randomized clinical trials, these plausible and consistent findings have changed my practice. I now actively promote remote monitoring to patients, and I choose devices that have wireless capabilities.

4. Aspirin Loses Its Mystique

Aspirin is one of the more common drugs I deprescribe. Numerous studies published this year urged us to think twice about using the old drug.

An analysis of the SPRINT-AF[11] Canadian registry revealed that 40% of AF patients treated with oral anticoagulants were taking antiplatelet drugs without an indication. I see this often. In the absence of recent stent placement, acute coronary syndrome, or the presence of a mechanical valve, there are no data to support combining these classes of drugs.[12] In fact, the combination increases the risk of bleeding. A Danish cohort study[13] of 37,464 hospitalized patients with heart failure and vascular disease found that adding antiplatelet therapy to vitamin K antagonists was associated with a higher risk of bleeding (HR = 1.31) but not with a lower risk of myocardial infarction or thromboembolism over a median 3 years.

The matter of aspirin for the primary prevention of CV events was debated this year. In May, the FDA issued a statement[14] concluding that the evidence does not support the use of aspirin for primary prevention. Then, in July, a European Society of Cardiology working group published a position paper[15] (in an American journal, JACC) recommending that aspirin be considered for primary prevention in cases where two or more major CV events were projected per 100 subject-years. Finally, at the American Heart Association (AHA) sessions in November, a Japanese research group presented a trial[16] of 14,464 high-risk patients in which aspirin failed to prevent CV events.

The problem I see with aspirin is not that it lacks benefit in some patients, but rather the misplaced view that it offers harm-free protection against untreated lifestyle factors. An obese sedentary patient recently told me that her doctor recommended aspirin "to take care" of her mild asymptomatic carotid thickening. I wondered (to myself) why better eating and exercise wasn't recommended, and why she even had undergone a carotid ultrasound.

5. Resistance to Board Certification Mandates

In putting together this year-end summary, I reached out to colleagues and asked them for a few of their top stories. This year, nearly everyone I spoke with cited the controversy over the new mandates from the American Board of Internal Medicine (ABIM).

A few clicks on the computer leads to ample evidence that the term "board-certified" may be on life support. The opposition to ABIM has moved from practicing physicians to state medical societies, and now, even the American Medical Association and the American College of Physicians have issued statements declaring that licensure should not be tied to maintenance of certification.

No reasonable person opposes the idea of having informed and capable doctors. The main problem I have with the new ABIM mandates is the utter lack of evidence that this brand of medical education provides benefit. It seems as though ABIM is exposing doctors and patients to a huge experiment.

Most doctors I know practice medicine in the real world—as a career and not a hobby. They work with real patients, in exam rooms and procedure suites. They make mistakes. They question, as do I, whether professional administrators can certify good doctoring. Suffice it to say that this is a big story, one that is just getting started.

6. Cardioversion Safety Revisited

There were two notable topics in cardioversion this year. In the first category of studies, Finnish investigators[17] addressed the risk of early (first 48-hours) cardioversion in 2481 patients with new-onset AF who were not taking anticoagulants. They found that shocking the patient earlier (12 hours or less) in the 48-hour window was better. My take, given the small but not insignificant risk for events (0.7%) after unprotected shocks, was to pause entirely and give (peace and) anticoagulants a chance to work.

On the matter of using new oral anticoagulant (NOAC) drugs before and after cardioversion, two studies brought good news. The X-VeRT trial[18] investigators found that rivaroxaban compared favorably to warfarin in 1504 patients with nonvalvular AF scheduled for either early or late cardioversion. There were no differences in a composite endpoint. Two patients in each group had postprocedure strokes.

Although the small number of events in the X-VeRT trial (a good thing) limited its statistical rigor, a substudy of the ARISTOTLE trial[19] bolstered the notion that NOACs can be used for cardioversion. In this analysis, ARISTOTLE investigators looked at 743 cardioversions done in 265 patients assigned to apixaban and 275 patients on warfarin. There were no strokes in either group (two patients died in each group).

7. Less Is (Still) More

Numerous studies published in 2014 reinforced the notion that less is more when it comes to practicing medicine. Here are few highlights.

In the treatment of patients with out-of-hospital cardiac arrest, basic—not advanced—life support increased the odds of survival.[20] And the long-held practice of giving epinephrine was associated with worse neurologic outcomes.[21]

In cardiac device implantation, the negative findings of the SIMPLE trial[22] disrupted standard practice by showing no significant difference in all-cause mortality with routine vs no defibrillation threshold testing at the time of implant.

In patients with persistent AF, the STAR-AF-2 trial[23] convincingly demonstrated that additional ablation beyond pulmonary vein isolation did not improve success rates. Less, not more, ablation—even in patients with advanced AF—proved the winner.

In the surgical treatment of patients with ischemic mitral regurgitation, adding a mitral-valve repair with coronary artery bypass graft (CABG) did not improve left ventricular remodeling, and the extra surgery increased adverse events.[24] In a similar vein, patients with severe ischemic mitral regurgitation (MR) referred for cardiac surgery got no benefit from the more complicated repair surgery compared with valve replacement.[25] Surgeons who took the tried-and-true simpler approach achieved a more durable correction of MR without compromising outcomes. (A brief sidebar on the treatment of valvular heart disease in 2014: An outside observer walking through a cardiac surgery unit might wonder what we are doing to the frail and elderly. I wonder, too: Are the regurgitant velocities and strain velocities obscuring our view of the human being?)

8. Progress in the Death-Denial Culture

A few words to provide context on the topic of death-denial in US healthcare: I see three major areas of misthink in the current approach to end of life. First, we view death as a failure rather than the natural end of all life. Second, we assume that most patients share our life-prolonging default. Third, we mistake the choice for quality of time over quantity as giving up. I've made these cognitive errors myself.

This year brought progress (dare I call it enlightenment) in how patients and doctors think about end-of-life care. Three events stand out.

The first was Brittany Maynard's choice to die on her terms. This triggered a discussion of the merits of physician-assisted suicide. But I don't see it that narrowly. Her decision stimulated an overdue conversation about avoiding a bad death. Ms Maynard taught the public—cardiologists included—that trading time for autonomy and dignity at the end of life was a logical decision.

The next two notable events came from literary works.

This year the famous surgeon and writer Dr Atul Gawande released his latest book, Being Mortal . There isn't space for a detailed review, but suffice it to say that the critically acclaimed and popular book may have started us on our way to improving the care of millions of human beings.

When Dr Ezekiel Emanuel wrote his controversial essay in The Atlantic, "Why I Hope to Die at 75," [26] he, too, accelerated an important national conversation about aging and mortality. I did not agree with his use of hyperbole, but he got people thinking about their goals of care as they contemplate end of life. Indeed, not ignoring this topic is a major step forward.

9. Guideline Decay

Cholesterol and blood pressure guidelines were published in 2013, but their effects made news in 2014.

Dr John Ioannidis (Stanford University) is what's known as a meta-researcher. His now-famous 2005 paper in PLoS Medicine,[27] "Why Most Published Research Findings Are False," launched his career as an expert on the credibility of medical research. In February 2014, he wrote an editorial in the Journal of the American Medical Association in which he estimated that, based on the new cholesterol treatment guidelines, more than a billion people worldwide could be taking statin drugs.[28] He wondered whether the "statinization" of populations "would be one of the greatest achievements or one of the worst disasters of medical history."

Ioannidis then offered numerous reasons why an area with extensive amounts of data and published clinical trials still lacked crucial evidence, saying a "leap of faith" would be needed to clinically interpret the modeling efforts of the current guidelines.

A few months later, Dr Harlan Krumholz (Yale University), also writing in JAMA,[29] provided perspective on a path forward with the new guidelines. Krumholz takes the view that the new cholesterol and blood pressure guidelines are revolutionary because, unlike previous statements, they express less certainty, emphasize the limits of evidence, and incorporate the role of the patient. These documents begin the paradigm-changing thinking that there is rarely a "right-answer."

An example of tone change in guidelines came from the 2014 AHA/ACC/HRS AF treatment guidelines,[30] in which the Class I recommendation for beginning anticoagulation says this (emphasis mine): "In patients with AF, antithrombotic therapy should be individualized based on shared decision-making after discussion of the absolute and [relative risks] of stroke and bleeding and the patient's values and preferences."

Here are three reasons why it's a good thing that guidelines are evolving away from being dicta: Consider the use of perioperative beta-blockers. Substantial contributions to the supporting evidence had been discredited because of scientific misconduct, while the remaining data suggested possible harm.[31] Yet, the change to guideline recommendations came slowly, and maybe only after crowdsourcing efforts from the community at large.[32] Second, University of Pennsylvania researchers analyzed 619 index recommendations from 11 guideline statements.[33] They found that durability of Class I recommendations varied across documents, and downgrades, reversals, and omissions were most common among recommendations that were not supported by multiple randomized studies. Third, and most damming of guidelines, was dronedarone's rise to prominence. Italian researchers compared the recommendations of three guidelines with their own conclusions about dronedarone by applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) and questioned not only the reliability of the clinical practice guidelines, but also the financial associations between many of the panel members and the manufacturer of dronedarone.[34]

10. The Blind Spot of Cardiology

Four in five heart attacks are preventable. These were the beautiful findings of Swedish researchers who studied the effects of five modifiable health measures in 20,721 men from 1997 to 2009.[35] No, lipoprotein(a) levels were not among them. Instead, this group measured the benefits of eating a healthy diet, drinking two (or fewer) alcoholic drinks daily, exercising regularly, having a small belt size, and not smoking. Each factor incrementally lowered the risk for first myocardial infarction, and those men who achieved all five measures were 79% less likely to have a heart attack than those who accomplished none.

Women, too, can prevent heart disease. American researchers performed a similar analysis of data from the Women's Health Initiative.[36] In this study, basic health parameters predicted heart failure risk. Over the 11-year follow-up, including 1826 incident cases of heart failure, women who ate well, exercised regularly, maintained a healthy body mass index, and did not smoke enjoyed a 77% lower risk of having heart failure.

Perhaps the strongest support that simple lifestyle factors are potent elixirs for health came from data on AF ablation results. In the ARREST-AF trial,[37] a team of scientists from Australia showed that patients enrolled in an aggressive risk-factor modification clinic increased their chance of ablation success fivefold.

These studies, which yield utterly expected findings, should alarm this generation of caregivers. While we perseverate over statin drugs, or ezetimibe with statin drugs, or cholesterol-efflux capacity, we are witnessing the first group of adults who can expect to live shorter and sicker lives than their parents. This, on our watch. Doctors can't change society alone, but we are health professionals, right? We can start by assessing the right health measures. The word that comes to mind is leadership.

That's it for 2014. Please feel free to agree or disagree with my choices in the comments section.


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