COMMENTARY

Top 3 Cardiology Trials of 2019

Prof Mamas Mamas

Disclosures

December 24, 2019

This transcript has been edited for clarity.

Hi, my name is Mamas Mamas. I'm professor of cardiology at Keele University, and welcome to Medscape. Today we're going to talk about the top trials of 2019. Which trials in my view have made an impact on clinical practice?

These aren't really in any particular order, but rather just the order that I chose to talk about them in.

DAPA-HF

So the first one I want to talk about is the DAPA-HF trial, one of the real landmark trials in heart failure.

So we know that SGLT2 inhibitors in randomised controlled trials in patients with cardiovascular disease have been shown to reduce heart failure admissions. So the premise of this trial was to look at whether patients with heart failure have better outcomes with dapagliflozin (Forxiga, AstraZeneca).

This was a randomised controlled trial in 4500 patients with heart failure and an NT pro-BNP of greater than 600. The patients were randomised either to standard heart failure regimes or to the SGLT2 inhibitor dapagliflozin. The inclusion criterion was a reduced ejection fraction of less than 40%.

The primary outcome was worsening heart failure or death from cardiovascular diseases. And this was reduced by 25% in the dapagliflozin arm.

Now, this is a really important trial. Why? These patients were optimally managed with state-of-the-art medications, 10% had Entreso (Novartis), over 95% of these patients were on beta-blockers, and 60-70% were on ACE inhibitors.

So this was a well-managed cohort, and dapagliflozin reduced the primary outcome, both in diabetic and in non-diabetic patients. Actually, there was no difference in outcome irrespective of diabetes status. Why is this important? Well, we know that heart failure admission is associated with poor prognosis and patients with heart failure have worse outcomes than many patients with cancer.

This trial shows that this medication, dapagliflozin, even in patients with optimal management, has a marked benefit on prognosis and will really change how we think about the management of heart failure.

I think it also will raise questions on who should start these medications. Dapagliflozin is a diabetic drug, but we seem to see efficacy in non-diabetic patients. I think this really is an important trial.

PARTNER 3

The second trial I want to talk about is the PARTNER 3 trial. Patients are becoming increasingly elderly. We see this in clinical practice all the time, and among the commonest valvular heart disease is severe aortic stenosis. TAVR (transcatheter aortic valve replacement) has been used initially in patients who were inoperable, then in high-risk then intermediate risk patients. So PARTNER 3 was asking the question whether patients at low-risk, according to Society of Thoracic Surgeons risk score predicted mortality of less than 4%, would benefit from TAVR compared with surgical aortic valve replacement (SAVR).

This was a non-inferiority trial, 950 patients were randomised either to SAVR or to TAVR, and the primary endpoint was death, stroke or all-cause hospitalisation. Initially this was randomised as a non-inferiority trial, but as a secondary endpoint, they assessed for superiority.

And this was really quite an interesting trial. Why? Because TAVR proved to be both non-inferior and superior to surgical AVR. So the primary endpoint in TAVR at 12 months was 8.5%, in the surgical arm it was almost double that at 15%. In the endpoints, there was significant reduction in bleeding, length of stay, stroke, and atrial fibrillation in the TAVR arm. Whereas, unfortunately, there was an increase in permanent pacemaker and moderate and mild paravalvular leak in the TAVR arm. Why is this trial interesting? Well, I think for the first time, it really makes us question what is the optimal management of patients with severe aortic stenosis who are low-risk.

This trial shows superiority for TAVR over surgery. I think we have to bear some things in mind, however. First and foremost, this trial only recruited patients where TAVR was possible through the transfemoral route. And we know that this is not always the case in patients with severe peripheral vascular disease. The average age of the patients was 73. And so I think, certainly for younger patients, there is a lot of questions to be asked.

And I think the most important discussion that has to be had about this trial is that we only saw 1 year endpoints. There isn't really a lot of good data around the much longer-term outcomes of this population. We know that these low-risk young populations have very aggressive valvular degeneration. And so 5, 10 years down the line, we simply don't know whether the outcomes of TAVR are going to be similar to surgical AVR or whether the event rates will cross over in favour of the surgical AVR arm.

Certainly, from my practice, I probably would undertake TAVR in more elderly patients. But I think in younger patients in my view, surgical AVR is very much the standard of care until we have longer follow up data in this group of patients with TAVR.

ISCHEMIA

The third trial that I wanted to talk about was the ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches). The ISCHEMIA trial was presented at the American Heart Association and this is the trial that everybody's talking about.

This was a trial of over 5000 patients from 320 sites from across the world. And it asked the question of whether patients with moderate to severe ischemia on stress imaging or exercise tolerance tests were better managed either with optimal medical therapy or optimal medical therapy and an invasive therapy.

Initially patients had a coronary CT to exclude left main disease and if they excluded left main disease they were randomised to either optimal therapy or invasive PCI.

The primary endpoint was cardiovascular death, MI, hospitalisation for heart failure, unstable angina, or cardiac arrest. The median follow-up was 3.3 years, and the primary endpoint was met in 13.3% in those managed invasively and 15% in those managed with optimal medical therapy.

So there was no difference in outcomes. Why is this important? Well, I think it really answers the question in patients with stable coronary artery disease that have a high burden of ischaemia that actually these patients have very good outcomes with medical management. There is no difference in hard clinical end points between undertaking PCI and medical management.

One thing that the trial did show was better symptom relief at 1 year with PCI and it certainly will help our discussions with patients that PCI, even in contemporary practice, won't make patients live any longer, won't reduce their event rates, but may help reduce their symptoms at 1 year.

I think the other thing that the ISCHEMIA trial really brings out is whether stress tests are necessary. After all, identifying ischaemia in these patients, [whether] moderate [or] severe, if you're not going to do anything about it, if you're not going to do PCI in these patients or use this as a means or as a target for revascularisation, then why do it? So I think certainly, in the coming couple of years, we should see a reduction in stress testing for ischaemia, particularly if now we're saying that in patients with severe ischaemia, there's no real indication to do PCI unless for symptomatic benefit.

Other Highlights

So thank you for joining me for my top three trials of 2019. There have been several other trials: COMPLETEISAR-REACT 5,  AUGUSTUS, but I thought that these three trials were the broadest and have the greatest impact on clinical practice. So thank you for joining me over 2019. I wish you and your families a very Happy Christmas and happy holidays. I wish you all the very best for 2020 and hope that you will join us in discussing trials and other interesting things on Medscape UK.

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