Food and Drug Administration Recall

 

Summary

The administration of Aprotinin during cardiac surgery reduces the amount of blood loss and preserves the platelets function. It also reduces the chances off a patient being transfused. Studies that have been conducted concerning the safety of the drug shows that it increases the number of cases of in-hospital deaths (Boer, 2018). The number of deaths in the Aprotinin receiving patients was higher than in those receiving other medications; thus it significantly links the medication to the mortality rate for those prescribed with it.

            The increase in mortality with use of the Aprotinin resulted into the suspension of a randomized study, and this was against the evidence that the drug was effective in the reduction of amount of blood lose during surgery and also reduce the chances of being transfused during cardiac surgery. However, there is little or no significant benefits that resulted from the use of the Aprotinin as compared to aminocaproic acid (Schneeweiss et al., 2008). This is supported by a meta-analysis that was done and found out that the use of the drug resulted in a decrease in the need for a blood transfusion, but there was no reduction in the mortality.

              Initially, data from the observational study was presented to the FDA advisory committee, but the advisory committee made recommendation favoring continued marketing of the drug. However, results from the Canadian randomized survey resulted in the suspension of the Aprotinin from the market (Boer, 2018). The study indicated that Aprotinin increased the risk of death compared to all other antifibrinolytic drugs that were used during the study. With the rise in the studies concerning the safety, the actions of the FDA have included changes in labeling and communications to physicians concerning the safety issues.

 

Clinical data review

Studies were conducted in the United States which involved four controlled studies, double-blinded which included five hundred and forty randomized patients that were scheduled for repeat of Coronary artery bypass graft. Out of the 540, 480 were valid for the effectiveness analysis. After obtaining the required sample, different regimens of  the treatment  were made use of in this study. Aprotinin Regimen A which included 2 million KIU intravenous loading dosage, 2,000,000 KIU introduced into prime pump volume then 0.5 million KIU hourly during the surgical procedure as an IV infusion.

Regimen B included 1,000,000 KIU intravenous loading dose, another one million KIU into the prime pump volume and 250000 KIU hourly as a continuous intravenous infusion. The placebo regiment involved the use of normal saline. The treatment regimen pooled all of the individuals or the Patients valid for the studies for efficacy analysis. In the pooled analysis, few patients that were on the Aprotinin regimen needed any blood donation when compared to placebo or pump prime only (Van Dooren, 2017). The amount in units of donor’s blood products transfused, the amount of donor’s blood transfused and the number in units required by patients significantly reduced in the patients that received Aprotinin as compared to those who received the placebo.

Evaluation involving pump prime regiment was done only in one study in both the primary and repeated Coronary artery bypass graft surgery patients. In addition, the difference between the two regimens involving the high doses and the other involving the low doses in terms of efficacy and the safety were not statistically significant.

Additional analysis in the subgroups showed no decrease in the benefit with the increasing age. There was a significant decrease in the amount in units of donor blood transfused to the clients both male and females. However, the number of the male sample was higher than female in the study which also showed that men did better considering the percentage of the people who required donor’s blood.

In a double-blind, randomized study that was done in Canada which compared the Aprotinin regimen A in the primary cardiac surgery patients who needs cardiopulmonary bypass who received prophylactic Trasylol within 48 hours prior to surgery to those who received placebo. The average blood loss for those who received the treatment was 1209.7mL compared to placebo 2532.3mL. The amount in units of red blood cells transfused also is low in the group that got treatment at 1.6 nits while for the placebo group it was higher at 4.3 units. This shows that the drug is effective

The data was collected well, and the information that was received was considered to promote the reliability of the data obtained during the study. Treatment of the group with a control group receiving placebo helps in coming up with accurate results. The double blindered randomized study promotes quality results. The findings of the data collected were not due to the patient or surgeon characteristics.

Data Monitoring Committee

In the study for the drug Aprotinin, there was a presence of the data monitoring committee which supervised the randomized studies that were done. For example, the study that was done in Canada. The findings of that study showed that the safety of the drug use for individuals undergoing cardiac surgery that required cardiopulmonary bypass was not acceptable because it showed an increased risk for death compared to the use of other antifibrinolytics. This raised a concern and led to the suspension of another random study and resulted in the withdrawal of the drug from the market and also the hospital.

Possibility of identification of adverse effect in the clinical phase

            It is a fact to state that the adverse effect of the drug to increase the chances of death in patients that are ready to undergo Coronary-Artery Bypass Grafting could have noticed during the clinical trial phase (Székely, Lex & Merkely, 2017). Unfortunately, the main focus during this phase could have been the benefits that it had. Most of the studies that have been done show that the drug is highly effective in the prevention of massive loss of blood and also reduces the chances of being transfused with donor’s blood.

            The attention during the clinical trial was focused on the benefits of the drug, and minimal attention was put on patient safety (Broomhead et al., 2016). The later stage where patients are put at higher risk for death could have been prevented if the trial were done in a considerate manner both focusing on the benefits and the adverse effects of the drugs. The study could have been broadened to cover all aspects of the drug.

            A good record of the individuals who received the drug as well as a good follow up both in the hospital an also at home would have been a stepping stone in understanding the trends of the drug, which will show the number of cases that occurred after its administration.  It was possible to note the association of the drug with increasing incidences of death through a proper understanding of the patient life pattern after the drug administration.

 

 

What the sponsor could have done differently

            The sponsor plays a vital role in the provision of resources that could be used in the study to come up with a better understanding of the condition. Proper support financially would have allowed acquisition better study told and also hiring of enough members of the team. This could have promoted a better understanding of the condition and maybe more would have been discovered during the initial clinical phase and would have prevented the loss that could have resulted from the drug suspension.

            The sponsor could have also set the objectives of the study to include the side effects of the drug and their consequences. This would have directed the study personnel to carry out all the research during the clinical trial by becoming alert after administration of the drug to note any change. It would have also been necessary for the sponsor to partner with other health institution workers to allow for reporting of adverse effects and even consequences that could have come.

            It is not always possible to capture everything but doing different studies at different areas could also have facilitated the discovery of the increased mortality associated with drug use. More reports from different regions can be more reliable than doing it once and for all

 

 

References

Boer, C. (2018, April). Weighing the Evidence for Coagulation Therapies in Cardiac Surgery. In 19TH ANNUAL SYMPOSIUM (p. 9).

Broomhead, R. H., Myers, A. E., & Mallett, S. V. (2016). Clinical aspects of coagulation and haemorrhage. Anaesthesia & Intensive Care Medicine, 17(2), 86-91.

Schneeweiss, S., Seeger, J. D., Landon, J., & Walker, A. M. (2008). Aprotinin during coronary-artery bypass grafting and risk of death. New England Journal of Medicine, 358(8), 771-783.

Székely, A., Lex, D., & Merkely, B. (2017). Aprotinin: Pharmacological Benefits and Safety. In Reducing Mortality in the Perioperative Period (pp. 97-103). Springer, Cham.

Van Dooren, A. A. (2017). Clinical Research Monitoring: A European Approach. World Scientific.