ADVERSE EVENT: CHARACTERISTICS AND EXAMPLES - MEDICINE - 2025

The adverse events are one of the most important variables when clinical and follow - up studies are conducted to drugs and surgical procedures. An adverse event is understood to be any circumstance that occurs during the execution of a medical procedure or the administration of a treatment.

The safety and risk outcomes of the procedures are highly dependent on the data collected on adverse events, in addition to adverse reactions and sentinel events. These three concepts create confusion as they can overlap, although in reality they are not the same or have the same impact on security.

The adverse event can be predictable or unpredictable and may or may not be a direct consequence of the treatment or procedure carried out. In this sense, all adverse events - even those where there does not appear to be a cause-effect relationship with the drug or procedure - must be reported.

Only the evaluation of the accumulated cases will be able to establish whether it is a situation that could put the health of the people who need it at risk.

Difference between adverse event and adverse reaction

As already mentioned, the adverse event is any situation that appears during the administration of a drug or the performance of a therapeutic procedure, related or not directly to it.

In this sense, it is very important to differentiate between adverse events and adverse reactions.

Adverse reactions are a type of adverse event

In adverse reactions, there is a causal relationship between the drug or procedure and the clinical consequence.

Adverse events are varied

Adverse events can be of all kinds. In addition to adverse reactions, they also include supervening events that in many cases can go unnoticed, as is the case of changes in certain laboratory parameters.

In addition, adverse events are considered comorbidities (secondary diseases that appear during the course of treatment) and even situations of daily life, such as a fall.

It is clearly something important, however difficult to understand, so it will be illustrated with several examples in order to facilitate the understanding of this concept.

Example

Imagine that during a clinical study of the MED-X drug used to treat anemia, a group of 20 patients was followed for a period of 10 months, keeping a detailed record of adverse events.

During this time, the registry returned the following results:

- One patient had a hypertensive crisis.

- Three people reported abdominal pain.

- A patient died during colon cancer surgery.

- Five patients suffered a fall from their own feet.

- One person required hospitalization for an asthma attack.

- Eight of the individuals presented elevated transaminase levels.

Analysis of accumulated cases

It is important to take into account that all adverse events must be analyzed from the pathophysiological point of view (causes of the event) and from the statistical point of view.

The first analysis is theoretical-conceptual and allows to lay the foundations for monitoring; for its part, the second is mathematical and may eventually lead to an adverse event changing its classification, as will be seen later.

Let's proceed with the conceptual theoretical analysis of MED-X adverse events.

- Hypertensive crisis

The MED-X drug is an iron compound used to treat anemia whose known mechanism of action does not affect in any way the systems involved in hypertensive crisis; thus, the hypertensive crisis is an unexpected adverse event, not associated with the drug.

- Abdominal pain

Three patients presented abdominal pain (a symptom), ultimately determining that one patient had stones in the bile duct, one suffered gastroenteritis and the third suffered abdominal pain of unknown origin, which subsided when the drug was discontinued.

In these particular cases the same adverse event (abdominal pain) can be classified in two ways depending on the scenario:

In the first two patients (gallbladder stones and gastroenteritis) this is an unexpected adverse event, not related to the administration of the drug. For its part, the last event (pain of unknown origin) is an unexpected adverse event, probably related to the administration of the drug.

The word probably is emphasized since it is a single case among several individuals, which does not allow establishing a causal association from a statistical point of view; hence the importance of long-term mathematical analysis, as will be seen later.

- Death from colon cancer surgery

In this case, it is very clear that it is an unexpected adverse event, not related to the drug, because the colon cancer was there before starting the drug and the surgery was an independent variable of the drug.

- Falls

Five patients suffered falls from their own feet. Since MED-X has no effects on muscle strength, central nervous system, balance or reflexes, it is initially an unexpected adverse event, not associated with the drug.

However, it is striking that it affected 25% of the patients, which makes it necessary to generate an alert for long-term follow-up of this adverse event. This event, as will be seen later, can change its characteristics.

- Hospitalization for asthma attack

In this case, it was a patient with a diagnosis of severe recurrent asthma from before the start of MED-X treatment, with a history of 1 or 2 hospitalizations per month for his underlying disease.

Taking this into consideration, hospitalization for the asthma attack is an expected adverse event (given the patient's history), not related to the medication.

- Elevation of transaminases

At this point, MED-X is known to have liver first-pass metabolism. In addition, it is known that in studies carried out in experimental animals it was shown that in large mammals (dogs) there was an increase in transaminase levels.

With this information in mind and considering that it was an adverse event that affected 40% of the patients studied (8 of 20), there are great possibilities of establishing a cause-effect relationship between MED-X and the elevation of transaminases; so in this case it is an expected adverse event, related to the drug.

Classification of adverse events

Until now, it can be deduced from the analysis carried out that there are at least two ways to classify adverse events: by the possibility of anticipating their occurrence or not, and whether or not they are associated with the drug or drug.

So the basic classification is:

- Expected or unexpected.

- Associated or not associated with the medication or procedure.

Initially, this classification is useful to establish the temporal and causal relationship, but it does not allow to determine the severity, something fundamental in safety studies.

Hence, all adverse events (expected, unexpected, associated or not associated with the drug) can in turn be classified based on their severity, as indicated below:

- Adverse event (AE) grade 1 or mild.

- AD grade 2 or moderate.

- AD grade 3 or severe.

- AD grade 4 or disabling / life threatening.

- EA grade 5 or is capable of causing death.

As can be seen, the recording, classification and analysis of adverse effects is a complex task and at the same time vital for the safety of therapeutic procedures. And this considering that so far only a part of their analysis has been studied.

Next we will see how adverse events are statistically processed.

Analysis of adverse events (accumulated data)

In addition to the initial description and registration, it is important to perform a statistical analysis of adverse events. As cases accumulate, this analysis can lead to unexpected findings or causal associations that had not previously been established.

Taking as a model the case of falls associated with the MED-X drug, it can be seen that the percentage of falls of the people who used the drug was high (25%), substantially higher than the percentage of falls in the general population (10- fifteen %).

If this trend continues, the staff responsible for therapeutic safety surveillance could hypothesize: "Is there a causal relationship between falls and MED-X use?"

To find an answer to this question, an ad hoc, double-blind controlled study could be designed to evaluate adverse drug reactions.

In this study, one group of patients is assigned to MED-X and another to placebo, and they are evaluated for a specified period of time, for example 12 months.

If at the end of the study the group that received MED-X had a significantly higher percentage of falls than the control group (that received placebo), the answer to the hypothesis is that there is a causal relationship; otherwise, that possibility is denied.

When the causal relationship is established

Suppose the causal relationship was established. At this time, two things can happen: the drug is withdrawn from the market (if it is already being marketed) and the reason for the drops is studied or, instead, a warning is placed on the package insert, safety recommendations are made and kept for sale, but still studied.

If it proceeds according to the second scenario, suppose that ad hoc studies are carried out and it is eventually determined that, when MED-X is administered, the metabolism of the drug induces an active metabolite that passes the blood-brain barrier and interacts with receptors at the cerebellum level., altering coordination.

At this point, the adverse event becomes an adverse drug reaction, because a causal relationship was established between an adverse event, initially apparently unrelated to the drug, and the administration of a given drug.

This process is continuous and constant for all therapeutic procedures and medical treatments. Hence, a given situation may change category as follow-up epidemiological studies are carried out.

These studies tend to span decades, providing data that allow optimizing the safety profile of all modern treatments.

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