Mandrola's Top 10 Cardiology Stories of 2016

John Mandrola, MD


December 22, 2016

1. Treatment of Left Main Disease

A feeling of reverential respect mixed with fear or wonder. This is awe. Awe is what I feel about the 2016 revelations on the treatment of left main disease with a percutaneous coronary intervention (PCI).

The best way to think about PCI vs coronary artery bypass graft (CABG) surgery is to make yourself the patient. Instead of having your sternum sawed open, your brain exposed to the heart-lung pump, and your body imprisoned in an alarm-ridden hospital ward for a week, you can get off a cath-lab table with a Band-Aid on your wrist and go home the next morning. That is the context in which I assess the EXCEL[1] and NOBLE[2] trials.

Don't be confused by the composite end points or the differences in the respective authors' conclusions. These big trials of drug-eluting stents vs CABG in patients with isolated left main disease basically showed the same thing—equivalence in mortality. You don't have to take my word for it. The chief justice of modern cardiology, Dr Eugene Braunwald (Harvard University, Boston, MA), wrote in an editorial in the New England Journal of Medicine that left main disease "can now be managed equally well by two strategies of revascularization if carried out by expert, experienced teams such as those participating in the EXCEL trial."[3]

The EXCEL and NOBLE trials call us to embrace our role as expert advisors and involve the patient in decision making. Although mortality was not statistically different in either trial so far, I accept that long-term results may slightly favor surgery and revascularization rates are higher with PCI. The thing is: people will value aspects of the two procedures differently. For some, a small separation of Kaplan-Meier curves at 5 years may be worth having the bigger procedure. For others, the idea of being "fixed" through a small puncture in the wrist looks better.

2. Lack of Benefit for ICDs in Nonischemic Cardiomyopathy and Anachronistic Guidelines

Prophylactic implanted cardioverter-defibrillator (ICD) use in patients with nonischemic cardiomyopathy (NICM) already rested on shaky grounds—a flawed meta-analysis that included patients treated with cardiac resynchronization therapy with defibrillator (CRT-D).[4] Before 2016, the number of trials with only nonischemic patients in which ICDs extended life was zero. After publication of the DANISH trial,[5] it's still zero.

DANISH investigators randomized about 550 patients with systolic heart failure due to NICM to standard care plus a prophylactic ICD or standard medical care alone. Standard care was exemplary, including CRT in 58% of both groups. After 67 months of follow-up, there were no significant differences in death rates. This replicated findings from the DEFINITE trial, which also found no statistically significant reduction in all-cause mortality for ICDs in patients with NICM.[6]

That ICDs don't extend life in patients with heart failure not due to ischemic disease is good news. The risk of death in these patients is lower in large part because of improved heart-failure therapy. In other words, we've helped these patients so much that protection against the small chance of sudden death doesn't lengthen life.

The DANISH trial also induces severe cognitive dissonance among clinicians who read the literature and then try to follow guidelines. That's because current practice guidelines recommend ICDs for patients with NICM.[7] Literature readers, however, know there are now two clinical trials that fail to show benefit of the ICD in patients with NICM. This problem exposes the anachronistic nature of static guidelines. Many months have passed since DANISH was published. If guidelines are to be useful, they need to incorporate new evidence much more quickly. Should a doctor seeing patients in 2016 be guided by expert statements published in 2008 (North American ICD guidelines), or a well-done, peer-reviewed and confirmatory trial published in 2016?

3. The Fall of Bioabsorbable Stents and FDA's Low Bar

In the summer of 2016, after the FDA approved the Absorb GT1 bioresorbable vascular scaffold (BVS) system (Abbott Vascular), I wrote a commentary that cited numerous studies[8,9,10,11] all hinting at higher rates of target lesion failure and stent thrombosis with the BVS. Hold on, said the BVS believers; you have to wait longer for the stent to dissolve and let the artery expand and regain its "vasomotor reactivity" to see the benefits.

A few months later at TCT 2016 we learned the 3-year results of the ABSORB II trial[12]—which Dr Sunil Rao (Duke University, Durham, NC) called a "bombshell." The shocker was that BVS proved inferior to standard drug-eluting stents (DES) for the very thing it's supposed to do—improve vasomotor reactivity. Worse, target vessel MI occurred in 6% of the BVS group vs 1% of the DES group.

The BVS flop exposes the problem with the FDA's low bar of approval of medical devices. As Rao noted in a discussion on on Medscape, "this is going to be a very challenging time because the bioresorbable stent is available now." Dr Robert Harrington (Stanford University, CA) responded by saying, "they [FDA] are going to have to address how to incorporate this new piece of information into what is already out there." These are medical leaders speaking carefully. I would say: the FDA screwed up and now it's hard to undo.

4. The Great Statin Debate

This year two leading medical journals, the BMJ and the Lancet, quarreled publicly over statins. The tussle began a few years ago when the BMJ published two articles critical of statin use in low-risk patients.[13,14]. Dr Rory Collins (University of Oxford, UK), from the Cholesterol Treatment Trialists' (CTT) Collaboration, then called on the BMJ to retract the articles, mostly because both papers used observational data to overestimate the adverse effects of statins. An independent panel exonerated the BMJ, and there was no retraction (corrections were made to both articles).

In September, the Lancet published an immense review article (over 300 references) from more than 25 of the world's leading statin experts[15]. In the 30-page paper, the authors made the case that statins deliver cardioprotection and have few adverse events and the public debate should stop.

Here is a direct quote: "Any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its underuse among individuals at increased risk of cardiovascular events."

Dr Richard Horton, editor of the Lancet, sided with the statin experts, likening public criticism of statins to the [measles, mumps, and rubella] MMR vaccine: "The debate about statins, as for MMR, has important implications for journals. Some research papers are more high risk to public health than others."[16]

There is a simple solution to this debate: the CTT collaboration should release their data for independent review.

5. The Best Statin Paper of 2016

Acrimony among academics should not overshadow one of the best papers of 2016; one which used the example of prophylactic statin therapy to study the distribution of life-span gain from a primary-prevention intervention[17].

Dr Judith Feingold (National Heart and Lung Institute, London, UK) and colleagues harnessed the power of math to calculate the probability distribution of life-span gained from statin use. They also went out into the public to assess how people evaluate potential gain from these therapies.

The Feingold et al paper changes the way we guide patient discussions about statin benefits. Rather than relay average gains in life-span or numbers needed to treat, these authors found that expected statin benefit is far from uniform. Although most people gain no added years from the intervention, a few gain far more than the average. And the difference in low- and high-risk people is not in the size of the life-span gain but the proportion who benefit. Provocatively, they noted more potential gain for younger people.

What's more, as described in "Prospect Theory,"[18] these researchers found that when people are given a choice on the chance of a gain from a primary-prevention benefit, some opt for the less mathematically optimal choice. Another reason for patient-centered decision making.

6. A Major Advance in Post–Cardiac Surgery AF

Estimates vary, but about two to four out of every 10 patients who undergo heart surgery develop atrial fibrillation (AF). That's a lot of people exposed to the dangers of doctors wielding rhythm-control therapies. I may be wrong, but increasingly, I worry more about AF treatments then the arrhythmia itself.

That's why I put the Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery[19]randomized controlled trial on this list. This study is an excellent example of a "negative" trial that delivers dramatic benefits. This 23-center trial compared the two strategies for postoperative AF, and, although the results were reported as negative (ie, no improvement from rhythm control), the equivalence in hospital days, rates of death, and adverse events allow doctors to stop the futility of trying to control AF in an acutely inflamed heart. At 60 days, more than 90% of both groups were free of AF.

The results of this study also support recent revelations in the pathogenesis of AF. People get AF after heart surgery because the heart is injured and inflamed. The atrial myocardium, the pericardium, and the autonomic nervous system are disrupted. The milieu of surgery caused the AF. It will pass. When it does, atrial health resumes. AF risk lessens. More and more, we are learning that atrial health determines the risk of AF. Make the atria healthier (weight loss, ideal blood pressure, better sleep, less alcohol), and it fibrillates less. If we had a hashtag for AF treatment in 2016, it should be #TreatTheCause.

7. Increased Uncertainty of Stroke Risk in Patients With AF

Quietly, without the boost of being a late-breaking clinical trial, a systematic review from a group of investigators from Beth Israel Hospital in Boston has shaken the core of one of the most fundamental principles of AF treatment—stroke prevention[20].

Think about this simple question: Why do we recommend people with AF take oral anticoagulant drugs? We do so because the drugs' absolute reduction of stroke risk outweighs the risk of bleeding. But even in high-risk patients, the absolute risk reduction from anticoagulation is small. (I dare you to look at a Cates plot [☺] on a decision aid.)

Numerous clinical trials give us a decent sense of risk reduction from anticoagulation, but what we have fooled ourselves into thinking we know is the untreated risk of stroke. As in, "Doc, what happens if I don't take the pill?" We look up numbers from the Northern European registries as if they hold for everyone: 2.2% annual stroke risk for CHA2DS2-VASc score of 2, 3.3% for a CHA2DS2-VASc score of 3, etc.

In a review of thousands of publications, the Beth Israel team found 34 studies that included patients with AF who were not treated with anticoagulants. Stroke rates varied widely but were mostly lower than the rates used in decision aids. The annual North American stroke rate was less than one-third that of the European rate (mean 1.3% vs 4.1%; P<0.0001), reaching a low of 0.45% in the US Women's Health Initiative. Stroke rates also varied threefold between prospective vs retrospective cohorts (1.2% vs 3.8; P<0.0001).

The reason this study deserves our attention is that dogma and quality measures say anticoagulation should be prescribed when untreated stroke rates are over 1% to 2% per year. But within each CHA2DS2-VASc score category, this review shows that stroke risk varies and may be lower than what we assumed. This lowers the absolute risk reduction of anticoagulation. It does not mean we shouldn't recommend anticoagulation, but it borders on hubris to think we know it is delivering net benefit in the millions of patients with AF and one to three stroke risk factors.

This study forces us to help patients get more comfortable with uncertainty.

8. Slow Uptake of New Heart Drugs

Available to cardiologists in 2016 are two new drugs (evolocumab[21] [Repatha, Amgen] and alirocumab[22][Praluent, Sanofi/Regeneron]) that dramatically lower LDL-cholesterol (LDL-C) levels and a heart-failure drug (valsartan/sacubitril [Entresto, Novartis]) that actually reduced mortality and hospitalizations in a randomized trial.[23]

Yet uptake of these drugs has been slow. So slow, in fact, that Dr Milton Packer (Baylor University), the PARADIGM-HF trial primary investigator, cited in an editorial in JACC Heart Failure, the late Nobel Prize-winning Colombian author Gabriel García Márquez's novel Love in the Time of Cholera in an effort to goad cardiologists to fall out of love with ACE inhibitors and angiotensin-receptor blockers (ARBs) and in love with valsartan/sacubitril.[24]

Magical realism notwithstanding, the reasons for slow uptake of new heart drugs are multiple. One is surely cost. Although the debacles of the EpiPen (Mylan) and pyrimethamine (Daraprim, Turing Pharmaceuticals) overshadow the price of heart drugs, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and angiotensin-receptor/neprilysin inhibitors (ARNI) cost a lot. And dollar costs aren't the only problem. In the US, payers of healthcare have erected barriers called prior authorizations. These are significant obstacles. One wonders if experts skilled in penning editorials and guideline statements understand that using new drugs in the real world is not as simple as writing a prescription. My office employs numerous humans whose sole job is to wrestle with payers. David only occasionally wins. Plus, the fact that doctors know there will be a fight is a deterrent as well.

I hope another reason for slow uptake of these drugs is critical appraisal of the evidence. Isn't it possible that doctors are awaiting proof that the LDL-C lowering of PCSK9 inhibitors delivers better outcomes? Similarly, in the matter of valsartan/sacubitril, do you think some prescribers put an asterisk on its win over enalapril because of the trial's run-in period, early termination, nonequivalence of angiotensin blockade in the comparator arm, and the side effects of hypotension and a hint of possible dementia risks?

9. Physician Burnout and Doctoring

When you are sick, you need doctors and nurses. You need their attention, their presence, their humanity. Yet one large study of nearly 7000 physicians found that more than half of them reported at least one symptom of burnout.[25]. This same study showed declining satisfaction with work-life balance. The nearer physicians are to the point of care of patients, the worse burnout gets.[26]

Confidence in one's own worth or abilities, self-respect, self-esteem, define morale. In 20 years of practice, I have never seen caregiver morale so low—both nurses and doctors.

Many factors play into the burnout and morale problem. It is wrong and lazy to blame the awfulness of the modern-day electronic health record—which is really just a billing system. The core cause of the morale problem is the commodification of healthcare. Commodification means transforming the care of people into a commercial enterprise. My partner jokes that doctoring has become similar to loading cones on the truck.

This is terrible. It causes us to lose good doctors before their retirement time. Hundreds of doctors and medical students commit suicide each year. In November, a kind, intelligent medical student, a friend with whom I worked, took his own life.

Something has to be done about burnout and low morale. People who run healthcare systems must understand that the delivery of healthcare cannot be reduced to commerce. The first step to caring for caregivers is to restore humanity and joy to their work.

10. Trump and the Future of Healthcare

When I traveled outside the US in 2016, nearly everyone wanted to understand our politics. "How is it possible?" Well, now it has happened.

In 2008, Americans were promised hope and change. For millions of Americans, the current administration delivered neither. In 2016, therefore, these people decided that their desire for change was enough to discount the outlandish things Mr Trump says.

The choice of Dr Tom Price, an orthopedic surgeon, Congressional representative, and critic of the Affordable Care Act, to lead the department of Health and Human services exemplifies the Trump dilemma. On the one hand, I disagree with Dr Price's opposition to Planned Parenthood, women's reproductive rights, and same-sex marriage. But on the other hand, I am ecstatic that a real doctor will lead a health department. It's hardly controversial to say we need more caregivers and fewer administrators running healthcare.

Trump's pick to run the Centers for Medicare and Medicaid (CMS), Seema Verma, is reasonable. The New York Times reported that she is a health policy expert from Indiana who helped Indiana expand Medicaid eligibility under the Affordable Care Act. Verma has also won praise from healthcare providers and legislators of both parties.

One thing is for sure: during my career the US healthcare system has underperformed and wasted resources. It favors overtreatment of the well and undertreatment of the needy. Our collective tolerance of such an unjust system is a national embarrassment. It's hard for me to believe this terrible system could be made worse. But perhaps it will. Democracy is something, isn't it?



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