DANAMI-2: PCI Still Beats Lysis in STEMI Even 16 Years On

Liam Davenport

September 02, 2019

PARIS — Patients with ST-segment elevation myocardial infarction (STEMI) transferred to an invasive center for primary percutaneous coronary intervention (pPCI) have better outcomes than those given fibrinolysis in their local facility even 16 years later, show long-term follow-up data.

The DANish Acute Myocardial Infarction 2 (DANAMI-2) trial was the first and largest randomized controlled trial to compare transporting patients with STEMI to have pPCI vs giving fibrinolysis.

The original results, published in 2003, showed that interhospital transport for pPCI was the superior strategy. This, combined with similar findings in other studies, led to recommendations that pPCI be performed if the time from STEMI diagnosis or first medical contact to reperfusion is 120 minutes or less.

Now 16-year results, combining the original findings with long-term registry data, were presented here at the European Society of Cardiology (ESC) Congress 2019 and simultaneously published online September 2 in the European Heart Journal.

They showed that pPCI was associated with a 14% relative reduction in the original composite endpoint of all-cause death, clinical reinfarction, or disabling stroke; a 25% reduction in reinfarction rates; and a 22% reduction in cardiac deaths.

Importantly, the technique led to an average postponement in the time to the first event of 12.3 months over fibrinolysis and an 11.5-months postponement in the time to first reinfarction.

Senior author Michael Maeng, MD, PhD, Department of Cardiology, Aarhus University Hospital, Denmark, said at a press conference that "physicians should feel confident that primary PCI remains the best way to treat STEMI patients, even after 16 years of follow-up, if transport can be achieved within 2 hours."

Mariell Jessup, MD, cardiologist and chief scientific officer at Leducq Foundation, Boston, Massachusetts, and chief science and medical officer of the American Heart Association, co-chaired a press conference where the results were presented here.

She told theheart.org | Medscape Cardiology that she would "applaud" investigators who conduct such long follow-ups of trials, as "too often" they are not available, and yet unexpected findings may emerge.

Here, she believes that follow-up curves are "really interesting" and the study "tells us much more about the pathophysiology" of STEMI.

Crucially, the curves for pPCI and fibrinolysis diverged early on during follow- up and then remained almost parallel.

"That means that the underlying disease process really doesn't change much" with PCI, Jessup said, but rather that the procedure "resets" cardiac function, after which the patients progress similarly in the two treatment groups.

Moreover, she underlined that this study was conducted with "old PCIs, not with fancy expensive stents," and yet the findings "still looked pretty good."

Landmark Trials

Maeng said that landmark trials in the 1990s, such as the Zwolle and PAMI studies, showed pPCI was superior to fibrinolysis in patients admitted to invasive centers.

This was followed by DANAMI-2, which involved 1572 patients with STEMI who were enrolled between 1997 and 2001, of whom 443 patients were from five invasive centers and 1129 were from 24 referral hospitals in Denmark.

Patients were randomly assigned following diagnosis of STEMI to reperfusion therapy with pPCI therapy at an invasive center or fibrinolytic treatment at the admission hospital.

Those admitted to referral hospitals were immediately transported to an invasive center if randomly assigned to pPCI, with a transfer time of 3 hours or less required from randomization until arrival at a catheterization laboratory.

All patients were immediately treated with aspirin and unfractionated heparin following the diagnosis, with those randomly assigned to fibrinolysis given a 15- mg bolus of alteplase followed by an infusion of 85 mg over 90 minutes on arrival at the hospital.

For pPCI, culprit lesions were stented unless the vessel diameter was less than 2.0 mm, and patients were treated with ticlopidine 500 mg daily for 1 month, until the PCI-CURE study was published, after which they were given clopidogrel 300 mg followed by 75 mg daily for 1 month.

Maeng said that, for the 16-year follow-up, they adopted a pragmatic approach, in which they gathered the 3-year follow-up data from the study and then linked the patients via their unique personal identification number to the Danish registries.

With data available on all-cause and cardiac death, as well as rehospitalizations for myocardial infarction, they were able to achieve an event detection rate of 89% to 100%, with an overall follow-up rate of 99.7%.

Overall, 60.0% of patients experienced a composite endpoint of all-cause death, clinical reinfarction, or disabling stroke, and 50.8% of patients died.

Analysis showed that patients who underwent pPCI had a lower rate of the composite endpoint than those who received fibrinolysis, at 58.7% and 62.3%, for an absolute difference of 3.6 percentage points and a hazard ratio of 0.86 (95% CI, 0.76 - 0.98; P = .022).

This translated into a mean postponement in the time to first event with pPCI vs fibrinolysis of 12.3 months (95% CI, 5.0 - 19.5).

Reinfarction rates were also lower with pPCI than with fibrinolysis, at 19.0% vs 24.5%, for an absolute difference of 5.5 percentage points and a hazard ratio of 0.75 (95% CI, 0.60 - 0.93; P = .008).

This equated to a mean delay in time to the first event with pPCI of 11.5 months (95% CI, 4.8 - 18.3 months) vs fibrinolysis.

When the researchers looked at all-cause death, they found no significant difference between the pPCI and fibrinolysis groups, at 50.5% vs 51.3%, for an absolute difference of 0.8 percentage points and a hazard ratio of 0.95 (95% CI, 0.83 - 1.09; P = .48).

Maeng noted, however, that "if we had stopped the evaluation after 10 years of follow-up, it would have been a significant result."

He told theheart.org | Medscape Cardiology that this result reflected the increasing impact of comorbid conditions on life expectancy.

"The average was 63 years at baseline and at 16-year follow-up it was 79 years old," he noted, adding that, "at that stage…you start dying of other causes."

This was reflected in rates of cardiac death being consistently lower in the pPCI group than in patients given fibrinolysis, at 18.3% vs 22.7%, despite the increasing mean age.

The absolute difference between the groups was 4.4%, at a hazard ratio of 0.78 (95% CI, 0.63 - 0.98; P = .035).

To examine the impact of transferring patients on long-term outcomes, the researchers analyzed the 1129 patients who were transferred from referral hospitals to invasive centers, finding that the results were broadly similar.

Compared with patients who received fibrinolysis, those who underwent pPCI had a hazard ratio of the composite endpoint of 0.82 (95% CI, 0.71 - 0.96), while that for reinfarction was 0.77 (95% CI, 0.60 - 0.98).

The hazard ratio for all-cause death was 0.91 (95% CI, 0.77 - 1.07) for pPCI vs fibrinolysis, and that for cardiac death was 0.79 (95% CI, 0.61 - 1.01).

Maeng told the press conference that, since the original DANAMI-2 study was conducted, practice in Denmark has changed in terms of how patients with STEMI are taken to invasive centers.

He said that at the time of the study, "patients were first transported to the local hospitals…then transported to the invasive centers."

"Nowadays that's changed," he continued, with patients diagnosed before they are transported; if STEMI is confirmed, the local hospital is bypassed and patients are taken straight to the invasive centers.

He said that a recent Danish study showed this approach reduced the transfer time by an average of 80 minutes.

Another notable benefit of transferring patients for pPCI, Maeng said, is that clinicians find that 20% of patients have other diagnoses and don't need a primary PCI but another intervention.

However, "the thing is that if you give fibrinolysis, you actually don't gain; you get the adverse events but you don't get any benefit for 20% of the patients."

Discussing the findings during their presentation, Borja Ibañez, MD, PhD, from the Spanish National Center for Cardiovascular Research, Madrid, underlined that the difference in cardiac death between pPCI and fibrinolysis groups was the most important finding.

He said that it may be explained by differences in rates of subsequent mechanical revascularization and rehospitalizations for myocardial infarction, which were lower for the pPCI group from the beginning of follow-up.

He noted that the ESC guidelines have reflected the importance of PCI, and the procedure is recommended for all patients who receive fibrinolysis, a practice that was not followed in DANAMI-2.

Consequently, Ibañ ñ ez said that the results refer to stand-alone fibrinolysis, and current practice should follow a combined pharmaco-invasive strategy.

The study was funded by Novo Nordisk Foundation and the Cardiology Research Unit at Aarhus University Hospital, Denmark. The DANAMI-2 trial (0- to 3-year follow-up) was supported by the Danish Heart Foundation, the Danish Medical Research Council, AstraZeneca, Bristol-Myers Squibb, Cordis, Pfizer, Pharmacia, Upjohn, Boehringer Ingelheim, and Guerbet (all Denmark). Pernille G. Thrane has received a scholarship from the Novo Nordisk Foundation and travel support from the A.P. Moeller Foundation. Steen D. Kristensen is supported by a senior research fellowship from the Novo Nordisk Foundation. Kristensen has received lecture fees from Aspen, AstraZeneca, Bayer, and BMS/Pfizer. Kevin K.W. Olesen has received speakers fee from Bayer. Thomas Engstrøm has received advisory board or speakers fee from Abbott, Merck Sharp & Dohme, and Bayer. Maeng has received advisory board or lecture fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim,  Novo Nordisk Foundation, and Boston Scientific. All the other authors report no conflicts of interest in this work.

European Society of Cardiology (ESC) Congress 2019. Abstract 4203. Presented September 2, 2019.

Eur Heart J. Published online September 2, 2019. Full text

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