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GISSI-3 Trial: ACE Inhibitors After MI Explained · This Is Why with Dr. Busti

• 0:00
  SPEAKER_00: When we talk about GISI3 trial, we're really talking about a moment in cardiology when clinicians were asking a very practical question.
• 0:11
  SPEAKER_00: Once a patient survives those first few hours of an acute myocardial infarction, what else can we do early to reduce death and limit ventricular damage?
• 0:26
  SPEAKER_00: Thombolysis was already in use, aspirin was already in use, but people were still dying, and many survivors were left with adverse cardiovascular remodeling and moving on to heart failure.
• 0:41
  SPEAKER_00: And so that was the gap that this study, the GIST3 trial, tried to fill.
• 0:47
  SPEAKER_00: Alright, guys, with that, I'm Dr.
• 0:48
  SPEAKER_00: Bustae, your host on This Is Why, where we take medical knowledge from knowing what to why so that we can meaningfully impact how we practice in healthcare.
• 1:01
  SPEAKER_00: In this series on landmark clinical trials, we're going to explore practice-changing studies like the Jizhi 3 trial within the context of the broader evidence so that we can better understand how and why they apply in real-world practice.
• 1:17
  SPEAKER_00: However, this isn't meant to be an exhaustive journal club.
• 1:21
  SPEAKER_00: Instead, our goal is to distill each study to its essentials and place it in the proper context so that we can better understand why we do what we do.
• 1:32
  SPEAKER_00: And so the question becomes does starting an ACE inhibitor, and in this case it's lysinopril, does starting an ACE inhibitor like a lysinopril very early after an MI actually help?
• 1:46
  SPEAKER_00: And is routine nitrate therapy also beneficial?
• 1:51
  SPEAKER_00: Now the GISC3 trial tested both in a very large pragmatic way.
• 2:00
  SPEAKER_00: More than 19,000 patients with suspected acute myocardial infarction were randomized within 24 hours in a two by two factorial design to receive lysinopril, nitrates, both lysinopril and nitrates, or neither across 200 coronary care units in Italy.
• 2:29
  SPEAKER_00: Now those treatments were given for six weeks.
• 2:33
  SPEAKER_00: So this was no tiny mechanistic trial.
• 2:37
  SPEAKER_00: This was a very real-world large-scale outcome study for its time.
• 2:44
  SPEAKER_00: Now think about why that design mattered.
• 2:54
  SPEAKER_00: They wanted a broad, acute myocardial infarction population, although they still did exclude some patients who would most likely crash or not do well on vasodilators or who had very severe heart failure.
• 3:10
  SPEAKER_00: So this was a pragmatic study, but it wasn't reckless.
• 3:16
  SPEAKER_00: It was asking what to do in a hemodynamically stable post-MI patient that's in front of you.
• 3:24
  SPEAKER_00: So here's the headline result.
• 3:27
  SPEAKER_00: Lysinerpril worked, but it was modest.
• 3:31
  SPEAKER_00: The six-week mortality was 6.3% with lysinerpril versus 7.1% without it.
• 3:41
  SPEAKER_00: So that's about an 11% relative reduction that resulted in a p-value of 0.03.
• 3:50
  SPEAKER_00: So it was statistically significant.
• 3:54
  SPEAKER_00: Now the combined endpoint of death plus heart failure or developing severe left ventricular dysfunction was also reduced with lysenter PRIL.
• 4:08
  SPEAKER_00: 15.6% of those patients on lysenter PRILL developed those versus 17% who did not receive an ACE inhibitor.
• 4:18
  SPEAKER_00: Now what about the nitrates?
• 4:21
  SPEAKER_00: Well, routine nitrate therapy unfortunately did not significantly contribute to an improvement in mortality or the combined endpoint.
• 4:32
  SPEAKER_00: Now that's important.
• 4:37
  SPEAKER_00: JITSI was not about a dramatic miracle trial.
• 4:43
  SPEAKER_00: The absolute mortality reduction was only 0.8%, which gave us a number needed to treat of about 125 over six weeks.
• 4:54
  SPEAKER_00: Now let's just pause there.
• 4:56
  SPEAKER_00: A number needed to treat of 126.
• 4:58
  SPEAKER_00: That means I have to treat over about 125 to 126 patients for six weeks on these treatments for one of them to benefit.
• 5:13
  SPEAKER_00: Is that worth it?
• 5:14
  SPEAKER_00: That's debatable, right?
• 5:16
  SPEAKER_00: Everybody's got their own opinion.
• 5:17
  SPEAKER_00: But in a disease as common and as lethal sometimes as myocardial infarction, a modest absolute benefit in a large population still matters to most.
• 5:38
  SPEAKER_00: Not from one enormous effect, but from stacking several modest, real benefits on top of each other.
• 5:47
  SPEAKER_00: Now why does this matter mechanistically?
• 5:51
  SPEAKER_00: Let's think about that.
• 5:52
  SPEAKER_00: Now this trial supported the idea that early ACE inhibition after MI is not just about blood pressure, isn't it, right?
• 6:03
  SPEAKER_00: It's about interrupting neurohormonal activation, reducing adverse remodeling, and lowering that risk and downstream burden of heart failure that can lead to sudden cardiac death.
• 6:19
  SPEAKER_00: Now, what about further follow-up data?
• 6:23
  SPEAKER_00: Well, the six-month follow-up is also helpful here.
• 6:27
  SPEAKER_00: So even after treatment was stopped at the six weeks, the combined endpoint at six months still remained lower in the lysinerpral group.
• 6:38
  SPEAKER_00: 18.1% versus 19.3%.
• 6:44
  SPEAKER_00: So that suggests that early biologic effect is still being carried forward.
• 6:51
  SPEAKER_00: Now let's take this one step further.
• 6:54
  SPEAKER_00: Who seemed to matter the most in this study?
• 6:58
  SPEAKER_00: Well, later analysis and expert summaries pointed towards greater benefit in higher risk groups, especially those patients with diabetes and anterior MI, and those with higher kilop classifications.
• 7:29
  SPEAKER_00: I mean, doesn't that fit with what we see clinically?
• 7:33
  SPEAKER_00: The higher the remodeling and higher the risk of heart failure, the more attractive early ACE inhibition becomes.
• 7:41
  SPEAKER_00: But we also need to be intellectually honest.
• 7:46
  SPEAKER_00: One aspect of the study is that it was open label trial.
• 7:50
  SPEAKER_00: It was also conducted in the thrombolytic era, not primary PCI era.
• 7:58
  SPEAKER_00: Now, if you also think about the background therapy that was different from what we use sometimes today, 72% of patients got thrombolytics.
• 8:08
  SPEAKER_00: 84% were on aspirin, and only 31% received beta blockers.
• 8:14
  SPEAKER_00: Furthermore, there was a few safety concerns, especially with hypotension.
• 8:20
  SPEAKER_00: And various summaries also mentioned obviously renal dysfunction concerns, which would be obvious issues with ACE inhibitors, right?
• 8:30
  SPEAKER_00: So you should not lift the exact absolute effect size from GISC3 and assume it applies unchanged to modern revascularized statin treated MI population.
• 8:41
  SPEAKER_00: But what changed because of this study?
• 8:44
  SPEAKER_00: GISC3 trial was one of the trials that helped normalize early ACE inhibitor therapy after MI as part of routine medical management, especially in stable patients and especially those at higher risk.
• 9:02
  SPEAKER_00: It also helped clarify something else.
• 9:06
  SPEAKER_00: Routine nitrate therapy, unfortunately, after MI is not a mortality strategy.
• 9:13
  SPEAKER_00: However, they can still help symptoms or ischemia.
• 9:17
  SPEAKER_00: But GISC3 did not support giving them across the board just to improve survival.
• 9:23
  SPEAKER_00: So how do we use this in today's current clinical practice environment?
• 9:28
  SPEAKER_00: Well, you may not cite GISC3 to say every single modern MI patient must automatically get lysinopril on the basis of this one trial alone.
• 9:39
  SPEAKER_00: We use it as part of the historical and evidentiary foundation for what current guidelines still support.
• 9:49
  SPEAKER_00: And that is that the blockade of RAS after acute coronary syndrome, particularly in patients with reduced EF, heart failure already, anterior MI, hypertension or diabetes, assuming that their blood pressure, creatinine, and potassium allow it.
• 10:08
  SPEAKER_00: So consider the patient in front of you again.
• 10:10
  SPEAKER_00: Who is that?
• 10:11
  SPEAKER_00: Well, it's a stable post-MI patient, most commonly with anterior infarct, diabetes, or mild left ventricular dysfunction, and an acceptable blood pressure.
• 10:25
  SPEAKER_00: Okay, GISC3 absolutely pushes you towards an ACE inhibitor early unless there's a contraindication.
• 10:33
  SPEAKER_00: What about a patient who is borderline hypotensive, in evolving shock, or a clear risk of vasodilation?
• 10:43
  SPEAKER_00: That's not the patient population that made this trial successful.
• 10:47
  SPEAKER_00: And the real issue is not whether ACE inhibitors are good drugs, but whether the patient at this moment can tolerate the adjustment and modulation of the physiology from ACE inhibitors.
• 11:00
  SPEAKER_00: And so the practical takeaway is this GIS E3 mattered because it showed early ACE inhibition after MI provides real, even if it's modest, mortality and remodeling benefit in stable patients, while routine long course nitrate therapy does not.
• 11:18
  SPEAKER_00: In modern practice, the lesson is not to treat everybody reflexively, it's to recognize that post-MI patient likely to benefit and start RAS blockade early when hemodynamics and the physiology can support it.
• 11:33
  SPEAKER_00: And that is this trial in its context, guys.
• 11:37
  SPEAKER_00: And on this is why our goal on this show is to move beyond what the data shows to understand why it matters so that we can apply it more effectively in clinical practice.
• 11:49
  SPEAKER_00: If you'd like a deeper breakdown of that trial, you can download the clinical trial handout outlining the study framework and key outcomes.
• 11:59
  SPEAKER_00: The link is provided to you in the description of the video on YouTube or our podcast channels.
• 12:05
  SPEAKER_00: It will lead you to thisiswhy.
• 12:08
  SPEAKER_00: Okay, where you can access that for free.
• 12:11
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• 12:24
  SPEAKER_00: We'll see you next time.