COMMENTARY

Sep 2, 2022 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

September 02, 2022

Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast on Apple Podcasts, Spotify, or your preferred podcast provider. This podcast is intended for healthcare professionals only.

In This Week’s Podcast

For the week ending September 2, 2022, John Mandrola, MD comments on the following news and features stories.

Revascularization in Ischemic Cardiomyopathy

Percutaneous coronary intervention or PCI is one of cardiology’s greatest modern achievements—when it is used to open an acutely occluded coronary during an MI.

But the use of PCI for any other coronary obstruction has never been shown to reduce MI or extend life compared with tablets. MASS-II, COURAGE, BARI-2D, ISCHEMIA were all null outcomes trials.

British investigators designed the REVIVED-BCIS, or REVIVED for short, to be the perfect set up for PCI to beat standard care.

Patients had left ventricular (L)V dysfunction (mean EF 27%) and severe multivessel CAD. The lesions had to amenable to PCI. And there had to be lots of myocardial viability.

Picture this patient in a cath lab.

Imagine a cardiologist thinking that these lesions were not important to fix.

This was the scenario in REVIVED. They randomized these patients to PCI or medical therapy. Over 3.5 years, there was not a shred of difference in the primary outcome of death or hospitalization for heart failure (HHF). The secondary outcome of improvement in LVEF also did not budge. And at two years, Quality of Life did not differ.

Comments:

The first thing to say about REVIVED pertains to the larger context: That is, whenever you think it’s not ethical to do a trial, you should think about REVIVED...and CAST, and the Woman’s Health Initiative, and COURAGE and the TTM trials or a list of about a 100 more. Randomized controlled trials are the greatest medical intervention of the modern era. Who, I mean who, would have thought that restoring blood flow without the early mortality signal seen in STITCH with CABG to weak but viable myocardium would not have budged outcomes?

I see two specifics on REVIVED. First is that it shows the power of medications. We cardiologists are doers. Fixing things firsthand gives us a rush of adrenaline and perhaps it is that rush that messes with our rationality. When we fix things, like blocked vessels, it feels more effective than mere pills. But statins and aspirin for CAD and the big four classes for LV systolic dysfunction form a high bar. These agents have all been shown to improve outcomes.

The second specific thing to say about REVIVED is that is yet more evidence that the clogged-pipe frame of modern cardiology is flawed.

Kudos to the King’s College London team—not only for their execution but more for their courage.

CV Screening in Men

I really love this job because it has great meaning to help people who are sick.

That last phrase is the key—people who are sick. Medicine is pure when we treat people with illness. But it is way harder to help people who have no complaints. In this case, we can only prevent things from happening in the future. That was the task that Axel Diederichsen and his Danish colleagues had in the DANCAVAS trial. They aimed to test whether a constellation of cardiac tests—delivered in a shockingly efficient manner—would improve survival. Not HHF, not CVD, but all-cause death. The point of any screening trial is not to reduce one kind of death—because there are infinite ways to die. The only endpoint of screening is survival overall. And they tested prevention in Denmark, a country known for its good health and good healthcare system.

45k men were identified and researchers randomized one third of them to an invitation to attend comprehensive cardiac screening and two thirds to no invite. Of those invited to screening, only 63%% attended. The main comparison was between the invited and uninvited.

The screening process was unique the whole thing took 40 minutes. On arrival to screening, participants completed a questionnaire then had their height, weight, and blood pressures in both upper and lower extremities (ankle-brachial index) measured. They then underwent a CT scan starting at the jaw and panning down to the femoral region. The scans assessed only for coronary artery calcium (CAC) and aortic aneurysms. A rhythm strip was taken during the scan. Then the patient had blood drawn for lipids and glucose. Technologists read the CT scans. No radiologists. Those with abnormalities, had follow-up visits and were offered lifestyle recommendations, smoking cessation advice, medications including aspirin, statins, and anti-coagulants, and vascular surgery. Follow-up via the national Danish health registry was planned for 10-years. This report was the 5-year update.

  • 12.6% of the screened group died vs 13.1% of the non-screened group. (HR 0.95 95% CI 0.90-1.00; p = 0.06).

  • Secondary outcomes, such as stroke, myocardial infarction (MI), aortic dissection and rupture all favored the screened arm.

  • Subgroups yielded provocative findings. Invitation to screening was associated with a significant 11% reduction in all-cause mortality in men aged 65-70 years but this was not in those older than 70 years.

  • Invitation to screening led to more prescriptions for antiplatelet drugs and lipid-lowering drugs (15% and 32%, respectively). There were no differences in use of percutaneous coronary intervention, coronary artery bypass surgery or vascular surgery between groups.

  • In a separate paper, the authors reported that the average difference in healthcare costs between the two groups was €207 per invitee.

Comments:

Despite its p-value, DANCAVAS was a positive trial. The majority of the 95% confidence interval includes a lower rate of death. Remember they measured death and nothing is materially different at p values of .06 or .04.

The subgroup showing men < 70 years did better persuades me: Slightly younger men would stand to benefit more from cardiac screening because they have fewer competing causes of death than older men.

A comment on translation of this trial: In DANCAVAS, the avoidance of overdiagnosis and overtreatment cannot be understated. There were no increases in cath, PCI or CABG in the screened group.

No one should be tempted to use DANCAVAS to support CAC screening outside of this setting. Diederichsen emphasized that Danish doctors do not feel compelled to look for ischemia in asymptomatic patients—even if they have a high calcium score.

The methodology and results of DANCAVAS should be studied and appreciated but not over-extended. It’s not a roadmap for what to do tomorrow—especially in systems outside of Denmark. Rather it’s a reason to question our status quo and plan more studies. This is what good science does.

Kudos to the investigators.

SGLT2 Inhibitors in HF With Mildly Reduced EF

Even before ESC, we knew from a press release that the trial met its primary endpoint of HF event and CV death.

At ESC, we heard the specifics. Recall first that EMPEROR-Preserved, a similar trial of empa vs placebo in HFpEF also met its primary endpoint but was driven by HHF without sig reductions in CV death.

The 6200-plus patients in DELIVER were 72 years old, 44% female, and 75% class 2 NHYA, with a mean EF 54%

The primary endpoint occurred in 16.4% of the DAPA group vs 19.5% placebo. The driver as in EMPEROR preserved was HF events.

Sadly, the DELIVER authors did not tell us at ESC or in the NEJM paper what total hospitalizations were

This is a real problem. Because In EMPEROR-Preserved, HHF represented less than 20% of total hospitalizations, which explains why the trial did not find a significant reduction in hospitalization for any cause.

Heart failure hospitalization can be an important surrogate endpoint only if its reduction is large enough to change total hospitalizations. This is generally the case for patients with reduced ejection fraction because HF is their dominant issue. But patients with HF and better ejection fractions are far more complex.

CV death was not significantly reduced. In fact, there were only 30 fewer CV deaths in this trial of 6200 patients. Overall death also was not significantly reduced.

Comments: Similar to EMPEROR-Preserved, DELIVER is technically a positive trial. DAPA reduced the primary endpoint of HF events, mostly hospitalizations, and CV death.

This is a good example of a positive trial of a fairly low-value drug. I say that as a user of SGLT2 inhibitors. The drugs have substantial benefit in patients with HFrEF, diabetes and chronic kidney disease.

But nearly all drugs have differential effects depending on the patient it is being used in.

Consider that when SGLT2i are used in the HFpEF, there is no reduction in death, no significant reduction in CV death. The only thing they do is reduce one type of hospitalization. In EMPEROR this was not enough to reduce total hospitalizations and in DELIVER, the authors don’t tell us.

Many of the same authors also published a meta-analysis in LANCET. Here they combined the two trials. And still no difference in overall mortality. Still no data on total hospitalizations.

My bottom line is that if SGLT2 inhibitors cost the same as furosemide, I’d be a proponent. Scientifically, there is probably a benefit in HFpEF, but the value at current prices is low.

We in the US have HUGE problems with disparities in access to care and outcomes. We spend more than any other country and this doesn’t translate to better outcomes. If we burn money in low-value uses, this worsens the healthcare equity situation. If I have a patient with HFpEF who has DM or CKD, I will use SGLT2i

If I have a patient with HFpEF who has no other indication, I won’t feel compelled to use the drug.

Anticoagulation in Rheumatic Heart Disease

Even though many of the listeners of this podcast, don’t see many patients with RHD, I really like this trial.

The global burden of RHD is substantial—it occurs most often in low-and middle-income countries, places where INR management is challenging. Direct oral anticoagulants (DOACs) have been shown noninferior to VKA in multiple trials—however patients with RHD were excluded.

RHD is different. It often leads to a high risk of atrial thrombus, more often affects younger patients and women. Most INVICTUS participants (70%) were women and the mean age was 50 years.

The theory here was that even if rivaroxaban was not potent enough in RHD, its simplicity of use in developing countries would allow it to be non-inferior to VKAs.

About 4500 patients were randomized from 138 sites in 24 countries in Africa, Asia and South America. The primary outcome was to be stroke or systemic embolism (SE), but the trialists noted that stroke rates were too low, partially because of increased deaths. If the endpoint were not changed, the trial would have been underpowered.

They then expanded the primary endpoint to include stroke, SE, MI or death from vascular or unknown causes. They used a noninferiority analysis and this is literally a perfect example of why NI should be used: namely, that even if rivaroxaban were similar or only a little worse, it offers the huge advantage of simplicity over warfarin.

The main results were 8.2% events per year in rivaroxaban arm vs 6.49% per year in VKA. The HR was 1.25 and the upper bound, or worst-case scenario was 1.41 or 41% worse and that was greater than the NI margin of 1.19.

The conclusion is obvious: we should continue to stick with VKA in patients w RHD.

I really want to congratulate the authors here. Kudos to the PHRI at McMasters, which does a shocking amount of research. Kudos to the leaders in developing nations, especially second author Dr. Ganesan Karthikeyan. You all have done a really meaningful thing.

Comments

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