10.4081/btvb.2022.24
In the Sixties, the few anti-thrombotic drugs available were administered following several criteria including tradition of the “School”, preference of the doctor in charge, pressure of pharmaceutical companies [...]
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Maria Benedetta  Donati
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Bleeding, Thrombosis and Vascular Biology
Antiplatelet drugs
The night of randomized clinical trials where all patients are black: a need to estimate variability in treatment effects
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Bleed Thromb Vascul Biol
Maria Benedetta  Donati
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10.4081/btvb.2022.24
Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli
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Di Castelnuovo A, Gialluisi A, Antinori A, et al. Disentangling the association of hydroxychloroquine treatment with mortality in Covid-19 hospitalized patients through Hierarchical Clustering. J Healthc Eng 2021;2021:5556207.
The night of randomized clinical trials where all patients are black: a need to estimate variability in treatment effects
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                                                                                                                        EDITORIAL

The night of randomized clinical trials where all patients are black:
a need to estimate variability in treatment effects
Giovanni de Gaetano,1 Chiara Cerletti,1 Licia Iacoviello,1,2 Maria Benedetta Donati1
1
 Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Italy; 2EPIMED Research Center, Department of Medicine
and Surgery, University of Insubria, Varese, Italy




              The order that our mind imagines is like a net,                 thousands of patients. Statistical analyses were performed
                   or like a ladder, built to attain something.               by both “intention to treat” and “drug efficacy” criteria.
             But afterward, you must throw the ladder away,                   Despite all these precautions, however, the results of dif-
             because you discover that, even if it was useful,                ferent trials were not always consistent but often contrast-
                                            it was meaningless.               ing. Thus, meta-analysis was introduced to overcome lack
                       (Umberto Eco, The Name of the Rose,                    of statistical power of individual studies and/or to identify
                       Picador Edition, Secker and Warburg,




                                                                                               ly
                                                                              a common denominator from different clinical contexts.1,2
                                     London, 1984, page 492)                  In subsequent years, “evidence-based” medicine was in-




                                                                                       on
                                                                              troduced to transfer the results of randomized clinical tri-
    In the Sixties, the few anti-thrombotic drugs available                   als (RCT) and meta-analyses to everyday practice.3,4
were administered following several criteria including tra-                        Therapeutic indications included in increasingly nu-


                                                                                  e
dition of the “School”, preference of the doctor in charge,                   merous guidelines or consensus conferences derived from
                                                                             us
pressure of pharmaceutical companies. Epidemiology and                        RCT performed on groups of patients who were seldom
statistics had not yet been fully developed and were not                      representative of the variability of the target disease and,
usually applied to therapeutic issues. Then, in the Seven-
                                                                             al
                                                                              even less, of the general population. Moreover, the bene-
ties, clinical trials started to be organized following pro-                  ficial effect of anti-thrombotic drugs ranged, at the best,
                                                          ci

gressively stringent criteria (the studies had to be                          between 20% and 40%: though statistically significant,
controlled, randomized, single or double blind, or cross-
                                                        er


                                                                              such an effect could also be (but was not) read as limited
over and so on) and should have involved hundreds or                          to relatively small groups of “responders”. As an example,
                                                       m




                                                                              out of 100 control patients with acute myocardial infarc-
                                                                              tion, 10 would have suffered another infarction or died
                                            om




                                                                              within one year; if a comparable group of 100 patients
    Correspondence: Chiara Cerletti, Department of Epidemiology and
                                                                              was given an anti-thrombotic drug, 3 would have bene-
                                                                              fited from the treatment (“responders”), while 7 would
                                     -c




    Prevention, IRCCS Neuromed, Via dell'Elettronica, 86077 Pozzilli
    (IS), Italy.                                                              have not (“non-responders”) and 90 would have been
                            on




    Tel.: +39.0865.915246.                                                    treated unnecessarily.5 This result was referred to as a
    E-mail: chiara.cerletti@moli-sani.org
                                                                              treatment-induced 30% reduction of the clinically relevant
                                                                              end-points under study.
                      N




    Key words: Randomized clinical trials, Individual variability, Ev-
    idence-based medicine, Personalized medicine, Antiplatelet drugs.              The problem was (and still is) that we were (and are
                                                                              still) unable to identify a priori the individuals who would
    Contributions: The authors contributed equally.
                                                                              get a benefit from those who would not or would even be
    Conflict of interest: The authors declare no potential conflict of in-    harmed by treatment. Moreover, the results of RCT were
    terest.                                                                   almost exclusively limited to counting the difference be-
                                                                              tween control and treated groups in numbers of non-fatal
    Funding: None.
                                                                              events or deaths. There was no mention or studies of un-
    Received for publication: 9 March 2022.                                   affected/surviving people in either group, nor whether the
    Accepted for publication: 9 March 2022.                                   observed events were similar or different in terms of likely
                                                                              pathogenetic/socio-cultural/life-style variables. Pharma-
    This work is licensed under a Creative Commons Attribution Non-
    Commercial 4.0 License (CC BY-NC 4.0).                                    cogenetic studies were still far to be introduced.6,7
                                                                                   RCT and related meta-analyses still today provide es-
    ©
     Copyright: the Author(s), 2022                                           timates of average treatment effects but are less suited to
    Licensee PAGEPress, Italy                                                 understand variability or heterogeneity of patients and/or
    Bleeding, Thrombosis and Vascular Biology 2022; 1:24
    doi:10.4081/btvb.2022.24                                                  treatment effects across individuals. Indeed, applying an
                                                                              average result of a RCT observed in a given study popu-

                                                Bleeding, Thrombosis and Vascular Biology 2022; 1:24
2                                                     G. de Gaetano et al.




lation to a specific patient would require an individual ho-
mogeneity that is not frequent in clinical practice.8              REFERENCES
    In recent years, newer machine learning methods have            1. Aspirin after myocardial infarction. Lancet 1980;1:1172-3.
been proposed to address heterogeneity of treatments and            2. Antithrombotic Trialists' Collaboration. Collaborative meta-
to predict individual variability.9,10 However, spurious re-           analysis of randomised trials of antiplatelet therapy for pre-
lationships within RCT data may occur that are not gen-                vention of death, myocardial infarction, and stroke in high
eralizable to other patients. Thus, future studies on                  risk patients. BMJ 2002;324:71-86. Erratum in: BMJ 2002;
                                                                       324:141.
machine learning approaches are warranted.
                                                                    3. Sackett DL, Rosenberg WM, Gray JA, et al. Evidence based
    Availability of real-life data derived from electronic             medicine: what it is and what it isn't. BMJ 1996;312:71-2.
health records, though based on observational studies not           4. Liberati A. Need to realign patient-oriented and commercial
allowing any causal inference, might produce comple-                   and academic research. Lancet 2011; 378: 1777-8.
mentary information to overcome some RCT limitations.               5. de Gaetano G, Cerletti C, Dejana E, Vermylen J. Current is-
    In conclusion, the results generated in the past decades           sues in thrombosis prevention with antiplatelet drugs. Drugs
by RCT allowed a tremendous progress in our strategies                 1986;31:517-49.
to prevent and treat ischemic cardiovascular disease,               6. Roses AD. Pharmacogenetics and the practice of medicine.
based on strict scientific criteria. The approach that was             Nature 2000;405(6788):857-65.
                                                                    7. Liuzzo G, Patrono C. Give genotype-guided dual antiplatelet
followed, however, appeared to be more similar to a uni-




                                                                                             ly
                                                                       therapy a second CHANCE. Eur Heart J 2022;43:938-9.
versal system with its sophisticated statistical rules, than        8. Angus DC, Chang CH. Heterogeneity of treatment effect:




                                                                                      on
to a system sensitive to every day clinical practice. The              estimating how the effects of Interventions vary across in-
real needs of individual patients were largely disregarded             dividuals. JAMA 2021;326:2312-3.
(a kind of philosophical contrast similar to that experi-           9. Athey S, Imbens G. Recursive partitioning for heteroge-



                                                                                e
enced in the 19th century between Hegel’s idealism and                 neous causal effects. Proc Natl Acad Sci U S A 2016;113:
Kierkegaard’s existentialism).
                                                                         us
                                                                       7353-60.
                                                                   10. Di Castelnuovo A, Gialluisi A, Antinori A, et al. Disentan-
    We should really and consistently estimate how and
at what extent the effects of interventions vary across in-            gling the association of hydroxychloroquine treatment with
                                                                  al
                                                                       mortality in Covid-19 hospitalized patients through Hierar-
dividuals to hopefully offer novel possibilities for shed-
                                                                       chical Clustering. J Healthc Eng 2021;2021:5556207.
                                                     ci

ding some light on the “epidemiological night” of RCT
and help develop a new individual evidence-based medi-
                                                   er



cine. Obviously, this will require new ways of thinking
and organizing clinical medicine.
                                                  m
                                         om
                                    -c
                             on
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                                     Bleeding, Thrombosis and Vascular Biology 2022; 1:24
