John Mandrola, MD


September 02, 2016

A tweet from the European Society of Cardiology (ESC) 2016 Congress lamented the lack of blockbuster results from this meeting.

That view wrongly assumes we need positive results to advance the field.

Cardiology is mature enough now that we should no longer expect results that massively change care. Consider the failure of what I call the ultimate do-over—regenerative therapy, or, said another way, the magical transformation of scar to normal heart. At the ESC meeting, two hot-line trials of stem-cell delivery missed the mark—which has been consistent with the stem-cell trend[1,2].

Another example of cardiology's maturity comes in this often-heard phrase: "The trial was underpowered to detect a difference." PRAGUE-18, a randomized controlled trial (RCT) presented during a hot-line session at the meeting, failed to show a difference between prasugrel (Effient, Lilly/Daiichi-Sankyo) and ticagrelor (Brilinta, Brilique, Possia, AstraZeneca) in patients with acute ST-elevation MI.[3] Some said the trial was underpowered to find the superior agent. I'd argue that's because both agents perform well, and acute coronary syndrome care is already superb.

The holy grail of cardiology comes in preventing acute closure of the vulnerable plaque in the first place. This remains elusive. The truth is we are not close. That's because it is basic lifestyle measures that promote endothelial and platelet health; and no pill, device, or sensors will change that. This truism does not bode well for industry or for those who desire blockbuster changes.

Arrhythmia care plods along on a similar plateau. Dr Mark Josephson (Beth Israel, Boston MA), writing in a recent editorial in Heart Rhythm, said he was "sadly disappointed in the progress of the past decade of electrophysiology."[4] The distinguished professor had hoped for a reawakening to the basics of arrhythmia mechanisms. Instead, he writes that "we obviously rely too much on technology without recognizing the limitations of that technology."

Since industry dominates research funding, I'm not optimistic for sweeping change. Slow uptake of His-bundle pacing is a good example. Namely, who will fund research that could decrease sales of cardiac resynchronization devices?

Negative Trials Teach Us a Lot

In the practice of medicine, knowing what does not work or what works equally well is valuable. The ESC meeting featured many of these sorts of trials. The DANISH trial, for instance, tells us that implanting a prophylactic ICD on top of maximal medical therapy in patients with nonischemic heart failure does not reduce the chance of death over the next 6 years.[5] We can debate age cutoffs, but DANISH represents the highest level of evidence, and it studied ICD therapy in the setting of contemporary heart-failure care. The option to discuss not using an invasive device, especially in the elderly, is a big advance.

NORSTENT is another ESC trial that could be mistakenly called negative.[6] In this comparison of bare-metal stents and drug-eluting stents (DES) for patients who present with stable or unstable coronary artery disease, one take might be that DES did not prove superior to bare-metal stents for the reduction of death or MI—thus, it's a "negative trial."

Interventionalists rightly pointed to the secondary results on target lesion revascularization (TLR). In absolute terms, DES reduced the chance of redo procedures at the site of the stent by 5%. I understand that a number needed to prevent a redo intervention of 20 is a big deal. It's possible that reduction could prove cost-effective.

But rather than focus on superiority of DES in one secondary end point, I would embrace NORSTENT's overall results: bare-metal stents deliver the same hard outcomes as DES. This result affects many patients. For instance, as an electrophysiologist in the southeastern US, a hotbed of atrial fibrillation, I advocate often for bare-metal stents. I use a lot of anticoagulant drugs; bare-metal stents appeal to me because they reduce the need for multiple antithrombotic drugs.

In an editorial accompanying the NORSTENT article in the New England Journal of Medicine,[7] Dr Eric Bates (University of Michigan, Ann Arbor) describes other groups of patients that may be considered for bare-metal stents: "Those with a large-vessel diameter in whom restenosis rates are low, those who cannot complete the longer duration of dual antiplatelet therapy recommended for drug-eluting stents because of noncompliance or need for noncardiac surgery, those who cannot pay for drug-eluting stents or a longer duration of dual antiplatelet therapy because of increased cost, and those at increased risk for bleeding."

One final note on NORSTENT. I think the results of this trial open up an opportunity for shared decision making. In patients with stable disease, we could say both stents provide a low risk of late stent thrombosis, an equal chance of avoiding death or MI, similar quality-of-life scores, and 95% of people would get the same results for target lesion redo procedures. (I call that the PSR—or percent same result; it's the inverse of the absolute risk reduction of 5%.)

I'm not saying patients should tell the cardiologist how to do PCI; but a decision aid shown to the patient before the procedure could help define a patient's perspective on risk of TLR vs the risk of longer-term antiplatelet therapy. Put me down as fearful of dependence on drugs that alter our body's exquisite balance of coagulation.

Celebrate Good Research—Not Its Results

I feel the same about research as I do about sports. The thrill is in the process, not the results. FDA commissioner Robert Califf recently reminded us that only 15% of guideline recommendations are backed by the highest level of evidence.[8] Published research that increases that percentage deserves our respect.

Many trials released at the ESC meeting included exemplary methods. In NORSTENT, for example, Norwegian investigators randomized more than 9000 patients from eight centers. They followed these patients for a median 59 months. Similarly, DANISH investigators enrolled more than 1100 patients with nonischemic cardiomyopathy from multiple centers, again, with a long follow-up of 6 years. Both these trials used legitimate and contemporary comparators—which increases their utility for real-world practice.

The DOCTORS study is a smaller randomized trial that studied the use of an expensive add-on imaging procedure to PCI—optical coherence tomography.[9] OCT changed procedural strategy in half the patients, and it led to modest improvements in post-PCI fractional flow reserve. I'm drawn to this sort of pragmatic study because it attempts to inform the utility of an expensive procedural add-on. We should celebrate this sort of work; for if we don't, we could end up with apocryphal notions of techniques deemed necessary for successful completion of procedures. Use of intracardiac echo for AF ablation comes to mind.

I will close with a study that did not make as many headlines but was beautiful in its methods, and it could have a massive effect on public health.[10] Brian Ference (Wayne State University, Detroit) presented a hot-line trial involving natural randomization—an intriguing method for transforming observational research into a randomized comparison­­­—of long-term exposure to both low LDL and low BP levels. Separate studies of this sort have previously confirmed the cardioprotective benefit of long-term exposure to low LDL alone and low blood pressure alone. In the HOPE-3 trial,[11] however, the combination of medically lowering LDL and BP did not prove statistically better than lowering LDL alone.

At ESC, during a hot-line session, Ference presented data confirming that the combination of low LDL and low BP exposure produced independent, multiplicative, and cumulative benefits. His findings, which included an analysis of more than 100,000 individuals, reached statistical significance because of long-term exposure to the favorable levels of LDL and BP. Patients in HOPE-3, he explained, were exposed to favorable LDL and BP for much shorter time periods.

Ference also stated, crucially, that these findings do not argue for drug-induced lowering of these markers as much as it does designing public-health interventions that provide early and sustained exposure to favorable LDL and BP levels.

I can't think of a better reason for parks, bike lanes, available healthy food, and more physical education in schools. If you want big gains in cardiovascular disease, these are the blockbusters of the future.



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