Fall in Hemoglobin Without Overt Bleeding May Be Prognostic in ACS

Even in the absence of a clinically obvious bleed, a hemoglobin drop signals a higher risk of 1-year mortality.

Fall in Hemoglobin Without Overt Bleeding May Be Prognostic in ACS

Among patients with ACS who are managed invasively, a drop in hemoglobin (Hb) during the initial hospitalization—even without a clinically obvious bleed—is associated with worse outcomes in the first year of follow-up, a post hoc analysis of the MATRIX trial shows.

Irrespective of the presence of an overt bleed, 1-year mortality was higher among patients who had a hemoglobin drop of at least 3 g/dL, although the relationship fell just shy of statistical significance for a major reduction in hemoglobin in patients without obvious bleeding, according to findings published online ahead of the February 2, 2021, issue of the Journal of the American College of Cardiology.

There are both clinical and research implications to the findings, senior author Marco Valgimigli, MD, PhD (University Hospital of Bern, Switzerland, and Cardiocentro Ticino, Lugano, Switzerland), told TCTMD.

“We now have a new tool to stratify the risk of patients, and now we know that we should probably assess Hb drop irrespective of the presence of bleeding, because that has the capability to give us additional information with respect to the patients that we are treating,” he said.

This is also relevant for clinical researchers determining appropriate sample sizes for studies, Valgimigli said. Because a hemoglobin drop without obvious bleeding is much more common than overt bleeding and has a similar relationship with 1-year mortality, its use as a study endpoint would allow for smaller, less-expensive studies to assess the effects of an intervention.

Impact of Bleeding Avoidance Strategies

Contemporary bleeding definitions are largely restricted to clinically overt events, using the degree of hemoglobin reductions to grade severity. According to the BARC classification, for instance, a fall in hemoglobin will not qualify as a bleeding event unless it’s accompanied by obviously apparent bleeding. Moreover, Valgimigli noted, falls in hemoglobin are “used in decision-making in an inconsistent manner” across centers.

To explore the prognostic significance of hemoglobin declines, the investigators turned to the MATRIX trial, which randomized invasively managed ACS patients to radial versus femoral access and to bivalirudin versus unfractionated heparin.

Of the 7,781 patients who survived at least 24 hours after randomization and had available data, 83.6% had a drop in hemoglobin during the initial hospital stay. Hemoglobin declines were classified as minimal (less than 3 g/dL), minor (3 to less than 5 g/dL), and major (5 g/dL or greater). Most patients with some decline in hemoglobin (88.5%) had no overt bleeding.

Minor and major falls in hemoglobin were seen in 15.1% and 3.5%, respectively, of patients with overt bleeding. The corresponding values in patients without obvious bleeds were 4.7% and 1.1%.

Minor and major reductions in hemoglobin were associated with greater 1-year mortality in patients with and without overt bleeding, although the confidence intervals around the estimates were wider in patients with clinically evident bleeds. Minimal declines in hemoglobin were not related to risk of mortality in either group.

Relationships Between Hemoglobin Drops and 1-Year Mortality



95% CI

With Overt Bleeding









Without Overt Bleeding









Of note, the bleeding avoidance strategies evaluated in MATRIX—radial access and bivalirudin—were associated with lower risks of both adjudicated in-hospital bleeding outcomes and minor/major hemoglobin declines.
As a continuous measure, each 1-g/dL decrease in hemoglobin was associated with an elevated risk of 1-year mortality in patients with and without overt bleeding (HRs 1.41 and 1.18, respectively).

Does BARC Classification Need a Rethink?

According to Valgimigli, the next studies to build on this one should explore how information about hemoglobin changes should be used moving forward—whether it should be used simply to risk-stratify or whether an action should be taken. Those answers can’t come from this study.

That said, Valgimigli highlighted the observation that efforts to minimize overt bleeding events through the use of radial access and bivalirudin also seemed to reduce minor and major drops in hemoglobin. This “basically gives us the signal that in many of these Hb drops without overt bleeding, most likely that is a blood loss which took place,” he explained. “The fact that interventions which reduced overt bleeding also reduced Hb drops basically makes the full story very sound by telling you that if you take overt bleeding plus Hb drops without overt bleeding you would need a much lower number of patients to test an intervention as compared to only taking overt bleeding.”

Asked whether the BARC classification should be reconsidered in light of this new information, Valgimigli, who participated in its creation, said: “If and when we will be reconsidering [the scheme], I think that information will be critical to update the BARC classification. I think that would be something that at least needs to be openly discussed. And the position taken in the old days of saying, ‘If there is no overt bleeding, a bleeding did not occur,’ probably needs to be revised.”

In an accompanying editorial, Olivier Barthélémy, MD (Pitié-Salpêtrière University Hospital, Paris, France), and colleagues say “it is important not to miss a prognostically important endpoint; however, care should also be taken to avoid overinterpreting a benign condition,” pointing out that “minimal Hb level variations are very common during PCI or ACS and are related to multiple factors, such as hemodilution, [periprocedural] loss, or hospital blood draws, but not bleeding.”

They congratulate the authors for the study, but say the value of including Hb drop without overt bleeding in current bleeding classifications remains an open issue. “The next steps are to take into account minimal Hb drop related to other conditions than bleeding and to confirm the most relevant threshold of Hb drop predicting cardiovascular outcomes,” the editorialists suggest.

Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • The MATRIX trial was sponsored by Società Italiana di Cardiologia Invasiva (a nonprofit organization), which received grant support from The Medicines Company and Terumo. This substudy did not receive any direct or indirect funding.
  • Valgimigli reports grants and personal fees from Abbott, Terumo, and AstraZeneca; personal fees from Chiesi, Bayer, Daiichi-Sankyo, Amgen, Alvimedica, Biosensors, and Idorsia; and grants from Medicure outside the submitted work.
  • Barthélémy reports travel and meeting support from Amgen, Bayer Healthcare, Boston Scientific, and Cardinal Health.