Charles C. Beasley, Jr’s: Final comment
Edward Shorter: The Q-T interval and the Mellaril story. A cautionary tale

Our knowledge of the etiology and pathophysiology of malignant cardiac ventricular tachydysrhythmias, including but not limited to Torsade de Pointes (TdP), has expanded exponentially over the last 20 years.  This expansion in knowledge is especially the case with those tachydysrhythmias due to either genetic variants resulting in cardiac ion channel dysfunction or drug/chemical interactions with these ion channels.  Stimuli for the research and knowledge expansion would include:  1) the unexpected results of the CAST study, conducted between 1986 and 1989, with final results published in 1991 (Echt 1991) showing that Class I antiarrhythmics (more specifically Class Ic agents that block the Na channel [I_Na] slowing depolarization but not affecting duration of the action potential), when administered to patients with PVCs following a myocardial infarction were associated with increased rather than the expected decreased mortality; and 2) the evolving recognition that terfenadine (blocks the rapid delayed rectifier potassium channels – I_Kr [hERG])  was associated with an increased incidence of sudden cardiac death due to TdP that evolved to ventricular fibrillation in patients consuming an inhibitor of cytochrome P450 3A4 (increasing plasma concentrations of terfenadine) with FDA issuing a warning in June 1990, FDA requirement for a warning letter from the sponsor to physicians in August 1990, FDA requirement for a Black box Warning in the Product Labeling in July 1992, and FDA recommendation for market removal in January 1997.

While QTc prolongation is a biomarker for risk of TdP and other ventricular tachydysrhythmias, even substantial QTc prolongation does not invariably lead to TdP.  Multiple drugs that prolong QTc are not associated with TdP including amiodarone, carvedilol, ebastine, loratadine, phenobarbital, ranolazine, salbutamol, tamoxifen, and tolterodine (Hondeghem 2008).  Additionally, drugs that prolong QTc can be antiarrhythmic, e.g., amiodarone.

The evolution of multiple experimental technologies, e.g., single cell patch clamp recordings that allow quantification of the blockade of specific cardiac ion channels, has done much to further our understanding of the genesis of these arrhythmias and the extent to which exposure to specific drugs might increase risk.

Hondeghem and colleagues (Hondeghem 2001, 2008a, 2008b; Shah 2005)  have proposed a set of four drug-induced changes (or characteristics of the changes) in cardiac electrophysiology that appear to be necessary to result in either TdP that can spontaneously revert to normal sinus rhythm (~80% of occurrences) or degrade into ventricular fibrillation (Vfib), or result directly in Vfib.  These changes in cardiac electrophysiology are best assessed through cardiac action potential studies in tissue preparations, but some have biomarkers that can be assessed on the surface ECG.

This set of changes referred to by the acronym of TRIaD.  The first of these changes is triangulation (T), the lengthening of ventricular action potential (AP) duration specifically by prolonging Phase 3 of the AP.  Triangulation will lengthen QTc that reflects the AP if Phase 2 of the AP (plateau phase) does not shorten.  However, triangulation will not lengthen QTc (or total duration of the AP) if Phase 2 is shortened.  Prolongation of Phase 3 repolarization is specifically defined as an increase in AP_30-90 duration in action potential studies (Shah 2005).  The ECG manifestation of triangulation is a widening and flattening of the T-wave (Shah 2005).  Such widening and flattening could be quantitated by measuring onset to end of the T-wave, the amplitude of the T-wave, ratios of these two parameters and absolute values of these two values. Phase 3 repolarization is strongly contributed to by potassium influx through the I_Kr channel, and blockade of that current can result in triangulation. 

The second factor, a characteristic of change is reverse use dependence (R) of the triangulation/prolongation of Phase 3 repolarization – greater effect at slower heart rates (Shah 2005).  A negative correlation between QTc length and heart rate would reflect reverse use dependence, but this cannot be assessed on a standard 10-second ECG although it might be assessed on an extended recording (Holter) if the recording interval captured a sufficient range of different, sustained heart rates.

The third alteration is temporal variability in the action potential duration on a cycle-to-cycle basis that is referred to as instability (Ia) (Shah 2005).  The ECG manifestation of instability is T-wave alternans (Shah 2005) that is a beat-to-beat change in the morphology of the T-wave, including its amplitude, sometimes so large as to result in alternating polarity of the T-wave.  Changes in width (including width from onset to peak vs. peak to end reflecting symmetry) and amplitude of the T-wave could quantitate such morphological change.

The fourth change is transmural dispersion (D) of ventricular repolarization (Shah 2005).  There is an ordered progression of repolarization across the ventricular wall initially with epicardial repolarization, followed by endocardial repolarization and finally M-myocyte (mid-myocyte, deep subendocardial) repolarization. Disruption and desynchronization of this sequence, particularly with M-myocytes is dispersion.  The ECG manifestation of dispersion is lengthening of the time interval between the peak and end of the T-wave, referred to as Tpe.  This length is sometimes corrected for QT (Tpe/QT).  Across the relevant literature, nomenclature is confusing because some authors refer to the absolute length as Tpe and some authors refer to that length corrected for QT as Tpe rather than Tpe/QT. 

TRIaD predisposes to the development of TdP that might or might not progress to Vfib, and to the development of Vfib without preceding TdP.  Other aspects of cardiac electrophysiology that can be influenced by drugs due to blockade of other cardiac ion channels (besides I_Kr) and alterations in autonomic tone, among other influences, predispose to the occurrence of Vfib in the presence of TRIaD.  λ is the product of the Effective Refractory Period (ERP) and Conduction Velocity (CV) (λ = ERP * CV).  The ERP is the time from the initiation of myocyte depolarization through partial repolarization (Phase 3) when stimulation will not result in a propagated AP (a second AP).  CV is the speed of transmission of depolarization.   As λ decreases, there is increased risk of Vfib (abrupt onset or evolution from TdP), and as λ increases, there is a greater likelihood of spontaneously terminating TdP (Shah 2005).

In general, most non-cardiac drugs that lengthen QTc, do so by blocking I_Kr and drugs that block I_Kr will often, but not always, be associated with all components of TRIaD.  Therefore, while not perfect, QTc prolongation can be used with some caution as a biomarker for risk of TdP.  One important exception to this general association between I_Kr blockade and TRIaD and risk of TdP is when the drug that blocks I_Kr also blocks Na and/or Ca channels as these pharmacological actions can offset the effect of I_Kr blockade.   QTc prolongation by itself is probably a poor basis for the decision to not bring a new chemical entity that might prove to be a valuable medication into clinical development.  In addition, it would be unwise to assume without question that individual case reports of sudden cardiac death or survived TdP in patients taking a drug known to prolong QTc “prove” that the event was due to the drug in the reported cases or “prove” that the drug causes such events.  At the same time, an ill-defined sufficient number of such cases reports must be considered a “signal” (suggestion of a possible effect) that must be carefully considered and evaluated.

As noted above, there are surface ECG parameters that reflect the components of TRIaD.  Unfortunately, with the exception of Tpe (and Tpe/QT), there are no data to suggest limits for these parameters that predict an unacceptable risk of TdP.  The data defining Tpe and Tpe/QTc limits are limited (Gupta 2008, Lubinski 1998, Shimizu 2002, Topilski 2007, Yamaguchi 2003).  QTc remains the one parameter where such limits (change from baseline and absolute value) have been defined on both a group and individual level with robust empirical support.

I found Prof. Shorter’s essay to be highly informative from a historical perspective.  I was not aware of the several studies dating back into the 1960s that did a reasonable job (by standards and methodologies available at the time) of quantifying QTc prolongation with thioridazine relative to other available antipsychotics.  Furthermore, I agree with him that action to inform the prescribing community, restricting use, and market removal were excessively delayed based on his summary.  The Pfizer comparative antipsychotic semi (no placebo control) – QT study (Study 054) (Harrigan 2004) probably completed in 1999 (Study 054 was the primary focus of an FDA Advisory Committee Meeting held in July 2000) was required to bring about definitive action for thioridazine (and mesoridazine).

In addition to the findings described by Prof. Shorter, QTc prolongation with an early after-depolarization superimposed on the preceding T-wave, the R-on-T phenomenon, (greater potential with QTc prolongation) has been recognized as a risk factor for a considerable period of time with the initial description in 1949 (Smirk 1949, 1960).  Therefore, any credible evidence of a substantial increase in QTc with thioridazine, relative to relevant comparators should have been carefully considered based on what I believe to be prevailing cardiac knowledge in the 1960s.  Interestingly, consistent with the theme of evolving knowledge, later review has suggested that R-on-T is not as malignant as one time believed (Engel 1978).

Are there additional potential confounds (besides the complexities of QTc prolongation versus TRIaD) when considering whether delayed ventricular repolarization was responsible for cases of sudden cardiac death temporally associated with thioridazine described by Prof. Shorter?  The short answer, based on the present (2017) knowledge, is yes (Koponen 2008).  Patients with schizophrenia suffer an increased prevalence of atherosclerosis, and myocardial ischemia/infarction and ischemia are the primary contributors to cases of sudden cardiac death through a malignant ventricular tachydysrhythmia.  Patients with schizophrenia evidenced decreased heart rate variability, an indicator of excess sympathetic to parasympathetic tone and this is also a risk factor for such arrhythmias.  Both of these risk factors could be secondary to drug treatment, but could be independent of drug treatment and due to genetic and environmental / lifestyle factors.

Additional factors could have complicated assessment of the evolving thioridazine data.  In 1953 chlorpromazine, also with QTc prolonging effects, was described as an antiarrhythmic (Simpson, 1987).  Death rate (but not specifically sudden cardiac death) before and after the introduction of modern psychotropic medication (antipsychotics, MAO inhibitors, tricyclic antidepressants, benzodiazepines, lithium) were compared with results suggesting no effect on these rates due to use of psychotropic medications in inpatient psychiatric facilities (Craig 1981).  Age-adjusted death rates among psychiatric inpatients before psychotropic medication introduction (3 cohorts: Norway – 1926-1941; Michigan – 1950-1954; New York – 1943-1944) were compared to the age-adjusted death rates for geographically and temporally comparable general populations.  The age-adjusted death rate for patients admitted to one New York psychiatric hospital between 1969-1977 was compared to the age-adjusted death rate for the relevant general population.  A comparison between death rates in the pre-psychotropic era versus psychotropic era leads to the interpretation that death rate had not been impacted by the introduction of psychotropic medication.   Interpretation of the findings of this study with regard to whether antipsychotics have or have not increased the incidence of sudden cardiac death are confounded substantially by not limiting analyses specifically to patients treated with only antipsychotics (or specifically thioridazine) and not limiting analyses to deaths classified as sudden cardiac death (unlikely that this level of detail was available in the records available to the researcher authors).  However, these findings would not be inconsistent with the possibility antipsychotics do not materially impact death rate in those patients treated with them.  As late as 1987, the official position of the American Psychiatric Association (APA) Task Force Report that summarized the interpretation of the extensive available data at that time by an expert group was as follows:

“Although a relationship between the use of antipsychotic drugs and sudden death has not been firmly established, it has also not been disproven.  From a neurocardiologic perspective, these drugs have the potential for both increasing and decreasing the risk of sudden death.  Ultimate outcome is probably determined by a multitude of interacting factors, and the role played by a drug in a given individual is difficult, if not impossible to determine.”

While this Task Force Report did note that “Thioridazine is the most frequently reported antipsychotic drug in terms of drug-induced cardiotoxicity and EKG changes,”  it did not single out thioridazine as an exception to the conclusion quoted above, a conclusion of uncertainty.

Multiple subsequent analyses (retrospective cohort analyses in large databases) have supported the hypothesis that antipsychotics are associated with an increased risk of mortality, for example, Ray (2001, 2009).

Unfortunately, I cannot say with any degree of confidence the extent to which the corporate sponsor medical staff responsible for safety assessment at the time of initial reports of QTc prolongation and sudden, unexplained deaths during thioridazine treatment were or were not aware of confounds and complexities that could impact the interpretation of these initial reports.  However, as described above, as late as 1987, an APA expert group concluded that a causal link between antipsychotic drugs as a class and sudden death was uncertain and thioridazine was not singled out as an exception.   As noted above, based on Prof. Shorter’s description of the evolution of data pertinent to thioridazine,  I believe that appropriate action on the part of the sponsor was excessively delayed. If I had better knowledge of all relevant information available to and considered by the sponsor as the data described by Prof. Shorter became available to that sponsor, I might couch my opinion in somewhat different language.  Additionally, I do not know the nature of any assessment that was made of a clear “signal,” or if any assessment was made at all.  From my perspective, an assessment was clearly warranted based on what I believe to be the prevailing cardiac “knowledge” at that time.

What factors might have led to lack of action (no/poor assessment or, in retrospect, incorrect interpretation of the data resulting from the best assessment possible at the time) on the part of the corporate sponsors of thioridazine?  There could be several such factors including, but not limited to commercial avarice, minimization of cognitive dissonance at an institutional level (neither individuals nor groups of individuals are particularly inclined to want to think ill of something for which they are responsible especially when they have invested considerable personal effort in bringing that thing into existence), and finally the complexity and confounded nature of the totality of relevant information available at any point in time.  Multiple factors could have combined to result in lack of action.

To me, the thioridazine story informs two very important lessons.  First, those responsible for the evaluation of the risks and safety of a drug product within the sponsor corporation must actively seek out and attend to every signal of potential risk.  Those signals must be thoroughly and objectively assessed without any regard to corporate profits and without any bias favoring positive interpretation over negative interpretation (avoidance of cognitive dissonance)  of the results of such assessments.  These assessments must employ all of the best tools available at the time of assessment, irrespective of cost.  Again, interpretation of the results of the assessments must begin from a neutral and agnostic position.  Appropriate action can then be taken.

Second, it is always easier to criticize in hindsight with additional knowledge that a signal was a signal of a real adverse effect.

Evolution of methodology has not only improved our ability to potentially understand the complexities of drug-induced delays in ventricular repolarization with the possibly ensuing risk of TdP and Vfib, but has improved our ability to assess the likelihood that a given adverse event is drug-related.  Electronic medical records and the compilation of large databases now provide a very powerful tool to perform retrospective cohort analyses such as those of Ray (2001, 2009).  While not prospective with random assignment to treatment (can establish association but not causation), they can be performed relatively quickly and are vastly superior to case reports and case series as well as databases of reports with unknown denominators (number of patients treated) (e.g., FDA FAES database).  However, such epidemiological studies do require that large numbers of subjects have been treated with the subject drug and this number grows as the rarity of the event of interest increases.  For an event that is actually caused by a drug, there will have to be a sufficient number of cases of the event caused by the drug and not caused by other things (background occurrence) to distinguish the statistic that aggregates occurrence in the drug group from that statistic for the control group.  Isolated case reports and possibly the recognition of biomarkers that might suggest risk are likely to come to light before there are sufficient raw data to conduct good retrospective epidemiological studies.

References

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January 25, 2018