Mandrola Previews His Top 5 Trials
From ESC 2022

John Mandrola, MD


August 22, 2022

Timing of Blood Pressure Meds

If you had high blood pressure and searched the internet for the best time of day to take your tablets, you'd come across the HYGIA trial — and you would be stunned. HYGIA compared daytime vs nighttime dosing of BP-lowering meds and found a 42% reduction of hard cardiac endpoints with nighttime dosing.

The plausibility case involves the observations that nighttime BP better predicts cardiac events than does daytime BP; and bedtime dosing of medications reduces morning BP, which might be important because cardiac events often cluster in the early morning. But 42% better?

At this weekend's European Society of Cardiology Congress in Barcelona, the first hot-line trial to be presented is called TIME, a trial in the UK in which 10,000 patients self-enrolled and were then randomized to take their BP-lowering medications in the morning or evening. The primary endpoint is a composite of MI, stroke, or vascular death.

TIME induces curiosity — for two reasons: first is that HYGIA has endured intense criticism about potential randomization errors and the implausibility of its effect size. If TIME comes back null, the argument for open data and independent review of source data gets stronger. The other reason to be curious: what if HYGIA was correct, and something so simple was hiding in plain sight?

Screening for Heart and Vascular Disease

I harbor many biases. Perhaps the strongest of these is that screening for disease helps the screeners more than the screened. Wilson and Jungner were prescient when more than a half-century ago they argued that screening for disease was admirable but in real life there were snags.

The snags of cardiac screening include imperfect screening tests, temporal declines in cardiac events, due to things like removal of trans-fats from foods, better baseline medical therapy (statins), and the inability of revascularization of screen-detected focal stenoses to reduce hard outcomes compared to medical therapy.

At this year's ESC, the DANCAVAS trial may finally disprove Wilson and Jungner and force me to change my mind.

DANCAVAS studies whether (truly) comprehensive cardiovascular screening will reduce death or cardiac events and, if so, is it cost-effective? The trial environment is unique because it will include only men (aged 65-74 years) who live on the Island of Funen — the third largest in Denmark with a population of about half a million people.

One third of the 45,000 men will be randomly assigned to a quite serious screening regimen that includes CT scans to assess for coronary calcium or aortic/iliac aneurysms, ankle-brachial index, cardiac rhythm assessment, and blood tests to measure lipids and glucose. The authors will use their national registry to assess all-cause death and costs. The control arm was standard care.

DANCAVAS turns on its control group. If the trial is null, or the effect size tiny, the proponents of screening will say the control arm was too good. If, however, DANCANVAS finds that screening reduces outcomes, and is cost-effective, well, that will be stunning, considering that Denmark is known for the health of its citizens and its laudable healthcare system.

Ischemic Cardiomyopathy and PCI

As an electrophysiologist, I often see patients with left ventricular dysfunction for consideration of an internal cardioverter defibrillator who end up having multivessel coronary artery disease. The obvious next question is: if these patients had better coronary flow, would that improve their LV function, reduce heart failure hospitalizations, and improve survival?

Yet the evidence for revascularization in patients with LV dysfunction is less than clear.

The STICH trial compared coronary artery bypass surgery (CABG) with optimal medical therapy in patients with ischemic cardiomyopathy and found no significant differences in the primary outcome of death. A potential reason for underperformance of CABG was its higher early death rate. Bolstering that idea was that long-term follow up, at nearly 10 years in STICHES, found a statistically significant death reduction with surgery.

What about percutaneous coronary intervention (PCI) rather than surgery? It's 2022, and PCI has benefited from many iterative improvements. It's unlikely to have the early mortality signal seen for CABG in STICH. It turns out that most of the trials comparing PCI vs surgery have excluded patients with LV dysfunction. In the largest trial, SYNTAX, only 2% of enrolled patients had significant LV impairment.

Enter the REVIVED-BCIS2 trial from investigators at King's College in London. They randomized about 700 patients with an LV ejection fraction (EF) ≤ 35% who have extensive coronary artery disease and viability in multiple segments to either optimal medical therapy plus PCI or optimal medical therapy alone. The primary outcome is death or hospitalization for heart failure.

Translation of these results will be tricky. These are highly selected patients (suitable anatomy and oodles of viability) who will get PCI from experienced operators, and follow-up is only 2 years. That said, I am intensely curious to see how well modern medical therapy matches up to modern revascularization. My bet is on medical therapy.

More Testing -- Just to Be Sure

I am old enough to remember the income-bolstering therapeutic fashion of doing repeated functional tests after revascularization.

While routine use of this strategy is now considered low-value care, there remains concern with patients who have had PCI of high-risk lesions — such as kissing stents in the distal left main. When I see such patients, I often think of platelets buzzing by all that metal in the left main coronary artery, 100,000 times each day.

This is why I am interested in the pragmatic POST-PCI trial, which randomly assigned more than 1700 high-risk patients who had undergone PCI one year earlier to either routine noninvasive stress testing or standard care. The primary outcome is a composite of death, MI, or hospitalization at 2 years.

In addition to the obvious clinical issue of whether routine surveillance with functional testing has any role in even the highest-risk patients, POST-PCI should also be examined for its exquisite attention to applicability in everyday practice. The authors used the PRECIS-2 score in designing the trial. This is a multi-domain measure of pragmatism (ie, are the patients representative, is the primary outcome relevant, is there flexible delivery of care, is the trial setting realistic?). We need more of this in trials.

Will Another Dogma Fall in Electrophysiology?

Some might argue with my decision to highlight the CAPLA study of pulmonary vein isolation (PVI) alone vs PVI plus posterior wall isolation in patients with persistent atrial fibrillation — because it doesn't have enough appeal to a general cardiology audience.

But I'm not choosing CAPLA because it will inform a technique for ablating persistent AF. I highlight CAPLA because if it fails to show a benefit to additional ablation beyond standard pulmonary vein isolation, it will demonstrate the utter dominance of evidence over eminence in guiding medical practice.

For over a decade, eminence has held that PVI alone is not enough for ablating persistent AF. So strong was this eminence that it survived the 2015 STAR-AF-II study, which found that additional ablation beyond PVI was no better than PVI alone in patients with persistent AF.

Nonrandomized studies of add-on posterior wall isolation have suggested benefit. Key opinion leaders have touted the additional ablation. Plausibility also favors posterior wall isolation because the area is rich in parasympathetic innervation and is a recognized site of potential triggers of AF.

CAPLA is elegant because it is simple: multiple centers will enroll patients, one group gets PVI, the other PVI plus posterior wall isolation. The primary endpoint is AF recurrence. I've never bought into the argument for initial and routine use of posterior wall isolation. This makes CAPLA another study from ESC that could cause me to change my mind. But…if CAPLA finds no benefit, then please don't argue with me the next time I suggest the need for proper randomized controlled trials.

For information on what else is in store at ESC, read Patrice Wendling's preview. This year's meeting is hybrid and I will be in attendance. If you are in Barcelona, say hello.

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John Mandrola, MD, practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. Follow John on Twitter.


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