Standard medical research leads to thousands of preventable deaths. How to fix it

In response to standard medical research practice, clinical care may change when a new study demonstrates the benefit of a treatment (or a harm, in which case the practice may be stopped). Standard medical research practice focuses instead on the latest research and does not routinely or systematically assess the state of knowledge. In this study, we used recent research on treatments for heart attacks to estimate the number of deaths that occurred because clinicians followed the standard research process. We show how a newer approach to medical research — cumulative meta-analysis, or “living systematic reviews,” might have saved those lives as well as unneeded research and cost, because the benefits (or harms) would have been known earlier.

A meta-analysis systematically combines the results of all studies on a given topic that meet specified criteria, and indicates the state of knowledge on this topic. Instead of knowing that, for example, two studies of the effects of aspirin on heart attacks found this, and five studies found that, etc., the meta-analysis gives an overall result. Meta-analyses are generally conducted when a researcher wants to know the overall state of knowledge in a field.

In cumulative meta-analysis, each time a new study is published that meets the specified criteria, it is added to an ongoing, “cumulative” meta-analysis, so that knowledge of the topic is routinely updated and knowledge on the topic is always current. Cumulative meta-analysis has been rare in medical practice, though it is becoming more common. Standards for the practice of cumulative meta-analysis have been formulated in a methodology of “living systematic reviews.”

In 1992, Dr. Elliott Antman and colleagues published a pioneering study demonstrating that knowledge of the effectiveness (or harm) associated with 15 interventions to reduce mortality among patients who had suffered heart attacks could have improved medical practice.(Antman, et al. 1992) They examined treatments both for patients immediately after their heart attacks and longer-term treatment during and following hospitalization. Antman and colleagues collected all the studies that had been conducted on these 15 interventions and retrospectively conducted a cumulative meta-analysis, so that they knew the year when knowledge of effectiveness (or harm) could have been known. The researchers also assessed year when these interventions were actually used in medical practice by examining recommendations in standard medical textbooks. They reported the delay in medical practice change that resulted because medical research had not used cumulative meta-analysis.

We (Hahn RA 2021) selected four interventions from the Antman study — intravenous vasodilators administered during hospitalization, and ß-blockers and aspirin administered during and after hospitalization, and one intervention found to increase mortality — Class 1 anti-arrhythmic drugs. We combined Antman’s findings on intervention effects with epidemiological data on the incidence of heart attacks in the U.S. in 1980 — the mid-point of Antman’s study, to estimate the number of deaths per year that occurred because of delayed intervention adoption, or, in the case of a harmful intervention, the number of deaths per year that occurred because of delayed intervention cessation. We also assessed the extent of research conducted that may have been unnecessary had cumulative meta-analysis been used.

Findings

In 1980, there were an estimated 95,000 in-hospital deaths from heart attacks, (15.2% of patients admitted to the hospital) and 137,000 post-hospital deaths (25.9% of patients discharged from the hospital). In the hospital setting, we estimated that the number of deaths associated with the non-use of interventions that would have been available had cumulative meta-analyses been conducted ranged from 12,000 per year for the non-use of intravenous or oral ß-blockers to 41,000 per year for the non-use of intravenous vasodilators (Table).

In the post-hospital setting, the number of deaths attributable to failure to use preventive measures that could have been available are 14,000 per year for the non-use of anti-platelet drugs (mostly aspirin) and 26,000 per year for the non-use of oral ß-blockers (Table). The use of type I anti-arrhythmic drugs was found to be harmful. Their routine use is estimated to be associated with 39,000 deaths per year (Table).

Delays in the use of effective interventions ranged from two years (for the use of aspirin in acute heart attack care) to 13 years (for the use of intravenous vasodilators in acute heart attack care). Failure to use prospective cumulative meta-analysis also resulted in a number of randomized clinical trials that were conducted after a significant effect could have been detected. The number of randomized control trials ranged from 2 (for aspirin and intravenous and oral ß-blockers in acute heart attack care) to 13 trials (for oral ß- blockers for hospital heart attack care). The number of patients enrolled in randomized controlled trials subsequent to a cumulative meta-analysis finding of benefit ranged from 296 (for aspirin in acute heart attack care) to 16,616 (for oral ß-blockers for hospital heart attack care).

Conclusions

The mortality costs of the failure to routinely conduct cumulative systematic reviews, i.e., “living systematic reviews,” are very high. There are other costs — the financial, opportunity costs, human costs of continued randomized trials when the basic question has already been answered, and the moral cost of not deploying the best available treatment.

The circumstances of heart attack have changed greatly since the period examined here. The incidence of heart attacks has declined, due partly to the interventions reviewed by Antman and because of changes in population behavior, e.g., smoking. Our purpose here is not to portray the current state of heart attacks, but to use historical data to indicate how the standard practice of science may severely hinder effective knowledge and practice and lead to unnecessary harm and unneeded research.

The process of building knowledge and applying it in medicine and public health needs fundamental revision. Ongoing cumulative meta-analysis should be routine, but requires a process to prioritize this approach and strengthen its methods. The development of living systematic reviews establishes an essential foundation for this project. The human cost of NOT routinely conducting cumulative meta-analysis is unacceptable.

Table. Annual Deaths Attributable to Non Use of Interventions for Heart Attacks in A. Acute Heart Attack Mortality in Hospital, B. Mortality Following Acute Heart Attacks

References

Antman, Elliott M, et al. 1992 A comparison of results of meta-analyses of randomized control trials and recommendations of clinical experts: treatments for myocardial infarction. JAMA 268(2):240–248.

Hahn RA, Teutsch SM. 2021 Saving Lives by Modifying the Process of Science: Estimated Historical Mortality Associated with the Failure to Conduct Routine Prospective Cumulative Systematic Reviews. Am J Biomed Sci & Res. 14(6).