Evaluation of Drug Effects on Cardiac Conduction
Ascribing clinical meaningfulness to lower degrees of AV block (AVB; first degree and type 1 second degree) is less clear compared with higher-grade AVB (type II second degree and third degree), which indicates advanced conduction system dysfunction. First-degree AVB is a term used to characterize AV conduction delay or slowing (rather than actual AV conduction block) and is manifest as PR (or PQ) interval prolongation, relative to normative values, typically beyond 200 to 220 ms, during sinus rhythm, at heart rates in the range of 60 to 100 beats/min in adults. Intermittent first-degree AVB and type I second-degree AVB (progressive PR prolongation preceding a nonconducted P wave), on the other hand, do not necessarily indicate an underlying pathologic condition and may be related to normal physiologic variations. Although lower degrees of AVB are often not clinically concerning, if they are drug induced, they may presage more significant AV conduction problems. Hence, drug-induced PR prolongation and AVB are often viewed as potentially deleterious. Many drugs resulting in slowing of AV conduction, such as β-blockers and calcium antagonists, are used routinely in high-risk patients with overt cardiovascular (CV) disease and in clinically appropriate patients who have net beneficial effect on CV outcomes. Nevertheless, in early-phase clinical studies, subjects with more than mild first-degree AVB (200–220 ms) or type I second-degree block at rest on screening ECGs might not be ideal for assessing potential drug effects, in particular for compounds with a possible preclinical signal on AV conduction. Subjects with more advanced AVB are typically excluded from early-phase clinical studies. A selected list of drugs associated with PR interval prolongation based on product labels (US full-prescribing information) is found in Table.
PR interval shortening has been reported with some drugs (eg, prucalopride and plerixafor), and variably short PR intervals may also be associated with increases in sympathetic tone, sympathomimetics, vagolytics, or sinus tachycardia. Cardiac conditions may also be associated with variable AV conduction, most notably the Wolf-Parkinson-White syndrome in which accelerated AV conduction via accessory AV pathways may result in short PR intervals and wider QRS complexes with appearance of initial δ waves, which correspond to ventricular preexcitation. Drugs may also affect conduction in these patients, making them less suitable for inclusion in early-phase studies.
A selected but not all inclusive list of drugs associated with PR interval prolongation is found in Table.
Drug-induced AV conduction delay frequently resolves shortly after discontinuation (eg, with β-blockers and calcium channel blockers). However, these changes often relapse in these patients, suggesting that drug-induced AV conduction disturbances may serve to uncover underlying conduction system disease. Such patients should be monitored carefully for signs of recurrent AVB. Clinical conditions associated with PR interval prolongation and AVB include hypothyroidism, infective endocarditis, ischemic heart disease, congenital conditions, iatrogenic causes (ie, postsurgery or interventional manipulation or ablation), and inflammatory or infiltrative disease (myocarditis, collagen diseases).
First-degree AVB was long thought to have a benign prognosis based primarily on observations from 2 large studies that evaluated about 5,000 healthy subjects. Subsequent investigations of 1,832 middle-aged men without known heart disease suggested that PR prolongation at baseline was often normalized at follow-up several years later and that progression to high-grade AVB over that time frame was rare. However, a recent analysis of 7,575 participants in the Framingham Heart Study, including older individuals and those with medical comorbidities, reported that prolongation of the PR interval was associated with increased risks of pacemaker implantation, development of atrial fibrillation, and all-cause mortality. Some limitations are inherent to the interpretation of this data set, including the potential of confounding association with PR interval prolongation with causality for adverse CV outcomes in different populations. However, these recent findings may suggest that the earlier data on the natural history of PR prolongation in young healthy men may not be representative of the prognosis of PR prolongation in older populations of patients, particularly those with concomitant illnesses such as coronary artery disease (CAD). Recently, it has been shown that PR interval prolongation was associated with higher risk for congestive heart failure and death in patients with stable CAD. Furthermore, these population studies suggest that elderly patients may be at higher risk for complications from drugs that affect AV conduction. First-degree AVB in healthy subjects in early-phase clinical studies cannot be considered to have the same clinical or prognostic importance as the same ECG finding in either middle-aged patients with underlying CV disease or CV risk factors, or in elderly patients with impaired cardiac conduction or overt or advanced CV disease.
Several factors can complicate the interpretation of PR interval changes as a surrogate marker for proarrhythmic risk in drug development. First, differences in ECG measurement and analysis techniques can increase the variability between serial measurements. Second, changes in physiologic conditions may contribute to intrasubject and intersubject interval variability in clinical trials, rendering causality assessments difficult. Variability related to circadian rhythms may be partly accounted for by heart rate and autonomic tone. The AV node is sensitive to changes in autonomic tone, and vagal stimulation slows AV conduction.
Finally, data from about 12,000 dECGs taken from healthy volunteers in phase I clinical trials of drugs not known to prolong the PR interval are concordant with PR interval values obtained from approximately 80,000 individuals included in pharmaceutical-sponsored clinical trials, as reported by Mason et al, and show that baseline-adjusted prolongation of more than 20% to 25% is rare, as is the shift from normal to high at a cutoff of 200 or 220 ms.
In type I second-degree AVB with narrow QRS complexes, conduction block is usually within the AV node and is observed in up to 1% of healthy young subjects, especially during sleep. Higher-degree/advanced AVB usually involves infranodal block and structural cardiac abnormalities and carries an increased risk for progression to complete AVB. The presence of relevant symptoms, advanced AVB, bradycardia with escape rhythm <40 beats/min, abnormally wide QRS complexes, ventricular pauses longer than 3 seconds, or a verified intra- or infra-His–located block are all risk factors for worse prognosis.
Type II second-degree AVB is very rare in healthy individuals. Normalization of AV conduction in subjects with type I second-degree AVB after awakening, during physical exercise or emotional stress, or after administration of atropine reflects the normal physiologic variability of AV conduction, whereas the lack of variability of high-grade AVB during an increase in heart rate is a pathologic and clinically relevant response that could be associated with a more serious clinical prognosis.
The nonclinical assessment of PR prolongation liabilities can be considered based on (a) cellular and subcellular experimental approaches and (b) interval recordings derived from tissues and in vitro or in vivo intact hearts. Subcellular methodologies used include measures of primary ionic currents involved in AV nodal excitability and conduction (including L-type calcium current, Cav1.2). It is possible to describe/predict the dromotropic effects of drugs based on the consideration of key individual ionic currents, but this approach has been used mainly to guide compound selection. Recordings from the regions of slowest or decremental conduction from the node may also be particularly relevant in delineating mechanisms of AVB (eg, extracellular electrograms or intracellular action potential studies). Such studies likely represent a more complete, integrated drug response that involves active and passive electrophysiologic components, changes in excitability, decremental conduction, simultaneous effects on multiple ion channels, and autonomic tone (eg, with β-blockers and cardiac glycosides). The first suggestion of dromotropic effects with evolving compounds is often discovered in the evaluation of PR intervals recorded in vitro or in vivo. Further details of dromotropic effects may be provided using His bundle electrograms to delineate the level of slowing or block in the AV node.
The preclinical evaluation of the effects of verapamil on the PR interval provides a useful example of translational studies. In vitro, verapamil prolongs the effective refractory period of the rabbit AV node and elicits rate-dependent slowing of conduction by reducing the amplitude of action potentials recorded from upper and middle nodal regions, consistent with its block of cardiac L-type calcium current (Cav1.2). In vivo, verapamil prolongs the PR interval in anesthetized and conscious dogs.
These preclinical findings are in agreement with clinical findings of concentration-dependent slowing of AV conduction and block at comparable concentrations. Differences in dromotropic effects across species may also be related to differences in ionic current densities within the AV node, receptor coupling to ion channels, autonomic tone, or differences in drug metabolism.
Selection Criteria and Clinical Monitoring During Clinical Trials
Healthy Volunteers If safety pharmacology studies are negative with respect to PR interval prolongation or AVB and there are no other relevant concerns based on structural/pharmacologic drug class considerations, it is probably safe to enroll healthy volunteers with first-degree AVB and second-degree AVB type 1 (when sleep associated). PR prolongation and AVB are then monitored according to standard cardiac monitoring for a clinical pharmacology study. It should be recognized that by causing R-R irregularity, AVB can compromise QT/QTc assessments if not properly recognized during study reviews. First-in-human studies are often expected to provide robust ECG evaluation, including PR interval.
On the other hand, if safety pharmacology studies are equivocal or suggestive of drug-induced PR interval prolongation or AVB or there is relevant concern based on structural pharmacologic drug class considerations, enrolling subjects with PR intervals ≤ 200 to 220 ms, without any evidence of second-degree AVB, might be advisable. There is increasing interest in making more effective use of high-quality early-phase ECG data to make earlier and more definitive assessments of drug exposure-response (and PK/PD modeling) and time course of effect characterizations of ECG effects, including PR, QRS, and QT/QTc intervals. Consequently, in early-phase clinical studies, subjects with more than mild first-degree AVB (200–220 ms) or type I second-degree block at rest on screening ECGs might not be best suited for fully assessing potential drug effects. For drugs with potential clinical effects, additional intensive CV monitoring, such as with real-time cardiac telemetry and Holter monitoring, can be added as warranted, to ensure volunteers' safety, profile relevant drug effects, and clear exposures intended for less monitored settings.
Patients Exposure margins in ambulatory patients are usually maintained below those found to be safe in healthy volunteers. The intensity of the clinical and ECG monitoring schedules should be guided by PK characteristics, administered comedications, associated morbidity, clinical feasibility, and possible CV conditions.
Exploring differences in relevant responses between healthy subjects and patient populations early in development can be very informative. However, individuals with relatively high probability of having underlying relevant CV conditions, with AVB, or taking concomitant medications that can cause PR interval prolongation are probably at higher risk for adverse events. Such patients could be excluded from clinical trials with investigational drugs that may adversely affect AV conduction until relevant exposure risk has been better profiled in healthy subjects, or in definitive CV studies. If definitive CV studies are not feasible, careful screening may be necessary to exclude subjects with moderate PR interval prolongation (eg, >220–240 ms), higher-grade AVB, or documented history of relevant symptoms (eg, syncope). It is important in patient trials, as well as in healthy volunteer studies, to exclude subjects who manifest accessory pathways, for example, ventricular preexcitation (δ waves).
Definitive ECG Studies With the possible exception of small-molecule oncology drugs and monoclonal antibodies, definitive ECG studies, or thorough QT/QTc (ECG) studies, are almost always required before expanded patient exposure in phase III clinical trials and provide robust ECG-based intervals analyses. Generally, the analyses from definitive ECG studies include the following:
Discontinuation of Subjects Dosing During Study Conduct Discontinuation decisions are modulated by the overall risk/benefit assessment and will often reflect the incomplete understanding of the risk posed by drug-induced AVB at the individual subject level. The following points can be considered when selecting criteria to define discontinuation relevant to AVB issues:
A.At the individual subject level
B.At the study cohort level
It is important to note that many subjects with AVB in early-phase studies will not have symptoms from the AVB, and if risk/benefit is appropriate, higher values for drug discontinuation may be warranted with ECG and subject monitoring and risk mitigation. For example, in many cases, subjects become relatively hypovolemic and, after prolonged recumbency and repeated blood draws and procedures, are more prone to vagal-mediated episodes that may include orthostatic hypotension, bradyarrhythmias, and various degrees of AVB, which can be minimized by keeping subjects hydrated and recumbent.
Event Management During Clinical Trial Conduct
Clinically significant PR interval prolongation and AVB observed during clinical events should be managed adequately to ensure subjects' safety. Individuals affected should be evaluated by an experienced physician. Blood sampling closest to the time of the event provides drug exposures, and clinical safety laboratory tests may rule out relevant undiagnosed conditions, for example, hypothyroidism. Additional history could uncover any unknown illnesses and medications intake that can affect the autonomic rhythm control, such as sympatholytic or vagomimetic drugs (eg, ophthalmic treatments are occasionally overlooked). This extensive evaluation will be useful for clinical study reports narratives requested by sponsor safety analysts and regulatory agencies.
The following adverse events probably represent outcomes potentially related to AVB and hence are informative to analyze when performing premarketing analyses of clinical trial data or postmarketing surveillance:
Part I. PR Interval Prolongation: AV Block
Clinical relevance of AV block
Ascribing clinical meaningfulness to lower degrees of AV block (AVB; first degree and type 1 second degree) is less clear compared with higher-grade AVB (type II second degree and third degree), which indicates advanced conduction system dysfunction. First-degree AVB is a term used to characterize AV conduction delay or slowing (rather than actual AV conduction block) and is manifest as PR (or PQ) interval prolongation, relative to normative values, typically beyond 200 to 220 ms, during sinus rhythm, at heart rates in the range of 60 to 100 beats/min in adults. Intermittent first-degree AVB and type I second-degree AVB (progressive PR prolongation preceding a nonconducted P wave), on the other hand, do not necessarily indicate an underlying pathologic condition and may be related to normal physiologic variations. Although lower degrees of AVB are often not clinically concerning, if they are drug induced, they may presage more significant AV conduction problems. Hence, drug-induced PR prolongation and AVB are often viewed as potentially deleterious. Many drugs resulting in slowing of AV conduction, such as β-blockers and calcium antagonists, are used routinely in high-risk patients with overt cardiovascular (CV) disease and in clinically appropriate patients who have net beneficial effect on CV outcomes. Nevertheless, in early-phase clinical studies, subjects with more than mild first-degree AVB (200–220 ms) or type I second-degree block at rest on screening ECGs might not be ideal for assessing potential drug effects, in particular for compounds with a possible preclinical signal on AV conduction. Subjects with more advanced AVB are typically excluded from early-phase clinical studies. A selected list of drugs associated with PR interval prolongation based on product labels (US full-prescribing information) is found in Table.
PR interval shortening has been reported with some drugs (eg, prucalopride and plerixafor), and variably short PR intervals may also be associated with increases in sympathetic tone, sympathomimetics, vagolytics, or sinus tachycardia. Cardiac conditions may also be associated with variable AV conduction, most notably the Wolf-Parkinson-White syndrome in which accelerated AV conduction via accessory AV pathways may result in short PR intervals and wider QRS complexes with appearance of initial δ waves, which correspond to ventricular preexcitation. Drugs may also affect conduction in these patients, making them less suitable for inclusion in early-phase studies.
A selected but not all inclusive list of drugs associated with PR interval prolongation is found in Table.
Drug-induced AV conduction delay frequently resolves shortly after discontinuation (eg, with β-blockers and calcium channel blockers). However, these changes often relapse in these patients, suggesting that drug-induced AV conduction disturbances may serve to uncover underlying conduction system disease. Such patients should be monitored carefully for signs of recurrent AVB. Clinical conditions associated with PR interval prolongation and AVB include hypothyroidism, infective endocarditis, ischemic heart disease, congenital conditions, iatrogenic causes (ie, postsurgery or interventional manipulation or ablation), and inflammatory or infiltrative disease (myocarditis, collagen diseases).
Prognosis of PR Interval Prolongation
First-degree AVB was long thought to have a benign prognosis based primarily on observations from 2 large studies that evaluated about 5,000 healthy subjects. Subsequent investigations of 1,832 middle-aged men without known heart disease suggested that PR prolongation at baseline was often normalized at follow-up several years later and that progression to high-grade AVB over that time frame was rare. However, a recent analysis of 7,575 participants in the Framingham Heart Study, including older individuals and those with medical comorbidities, reported that prolongation of the PR interval was associated with increased risks of pacemaker implantation, development of atrial fibrillation, and all-cause mortality. Some limitations are inherent to the interpretation of this data set, including the potential of confounding association with PR interval prolongation with causality for adverse CV outcomes in different populations. However, these recent findings may suggest that the earlier data on the natural history of PR prolongation in young healthy men may not be representative of the prognosis of PR prolongation in older populations of patients, particularly those with concomitant illnesses such as coronary artery disease (CAD). Recently, it has been shown that PR interval prolongation was associated with higher risk for congestive heart failure and death in patients with stable CAD. Furthermore, these population studies suggest that elderly patients may be at higher risk for complications from drugs that affect AV conduction. First-degree AVB in healthy subjects in early-phase clinical studies cannot be considered to have the same clinical or prognostic importance as the same ECG finding in either middle-aged patients with underlying CV disease or CV risk factors, or in elderly patients with impaired cardiac conduction or overt or advanced CV disease.
Variability of the PR Interval
Several factors can complicate the interpretation of PR interval changes as a surrogate marker for proarrhythmic risk in drug development. First, differences in ECG measurement and analysis techniques can increase the variability between serial measurements. Second, changes in physiologic conditions may contribute to intrasubject and intersubject interval variability in clinical trials, rendering causality assessments difficult. Variability related to circadian rhythms may be partly accounted for by heart rate and autonomic tone. The AV node is sensitive to changes in autonomic tone, and vagal stimulation slows AV conduction.
Finally, data from about 12,000 dECGs taken from healthy volunteers in phase I clinical trials of drugs not known to prolong the PR interval are concordant with PR interval values obtained from approximately 80,000 individuals included in pharmaceutical-sponsored clinical trials, as reported by Mason et al, and show that baseline-adjusted prolongation of more than 20% to 25% is rare, as is the shift from normal to high at a cutoff of 200 or 220 ms.
Second- and Third-degree AVB
In type I second-degree AVB with narrow QRS complexes, conduction block is usually within the AV node and is observed in up to 1% of healthy young subjects, especially during sleep. Higher-degree/advanced AVB usually involves infranodal block and structural cardiac abnormalities and carries an increased risk for progression to complete AVB. The presence of relevant symptoms, advanced AVB, bradycardia with escape rhythm <40 beats/min, abnormally wide QRS complexes, ventricular pauses longer than 3 seconds, or a verified intra- or infra-His–located block are all risk factors for worse prognosis.
Type II second-degree AVB is very rare in healthy individuals. Normalization of AV conduction in subjects with type I second-degree AVB after awakening, during physical exercise or emotional stress, or after administration of atropine reflects the normal physiologic variability of AV conduction, whereas the lack of variability of high-grade AVB during an increase in heart rate is a pathologic and clinically relevant response that could be associated with a more serious clinical prognosis.
Nonclinical Assessment of PR Interval Prolongation and AVB
The nonclinical assessment of PR prolongation liabilities can be considered based on (a) cellular and subcellular experimental approaches and (b) interval recordings derived from tissues and in vitro or in vivo intact hearts. Subcellular methodologies used include measures of primary ionic currents involved in AV nodal excitability and conduction (including L-type calcium current, Cav1.2). It is possible to describe/predict the dromotropic effects of drugs based on the consideration of key individual ionic currents, but this approach has been used mainly to guide compound selection. Recordings from the regions of slowest or decremental conduction from the node may also be particularly relevant in delineating mechanisms of AVB (eg, extracellular electrograms or intracellular action potential studies). Such studies likely represent a more complete, integrated drug response that involves active and passive electrophysiologic components, changes in excitability, decremental conduction, simultaneous effects on multiple ion channels, and autonomic tone (eg, with β-blockers and cardiac glycosides). The first suggestion of dromotropic effects with evolving compounds is often discovered in the evaluation of PR intervals recorded in vitro or in vivo. Further details of dromotropic effects may be provided using His bundle electrograms to delineate the level of slowing or block in the AV node.
The preclinical evaluation of the effects of verapamil on the PR interval provides a useful example of translational studies. In vitro, verapamil prolongs the effective refractory period of the rabbit AV node and elicits rate-dependent slowing of conduction by reducing the amplitude of action potentials recorded from upper and middle nodal regions, consistent with its block of cardiac L-type calcium current (Cav1.2). In vivo, verapamil prolongs the PR interval in anesthetized and conscious dogs.
These preclinical findings are in agreement with clinical findings of concentration-dependent slowing of AV conduction and block at comparable concentrations. Differences in dromotropic effects across species may also be related to differences in ionic current densities within the AV node, receptor coupling to ion channels, autonomic tone, or differences in drug metabolism.
Clinical Trial Design to Mitigate Risks Related to PR Interval Prolongation and AVB
Selection Criteria and Clinical Monitoring During Clinical Trials
Healthy Volunteers If safety pharmacology studies are negative with respect to PR interval prolongation or AVB and there are no other relevant concerns based on structural/pharmacologic drug class considerations, it is probably safe to enroll healthy volunteers with first-degree AVB and second-degree AVB type 1 (when sleep associated). PR prolongation and AVB are then monitored according to standard cardiac monitoring for a clinical pharmacology study. It should be recognized that by causing R-R irregularity, AVB can compromise QT/QTc assessments if not properly recognized during study reviews. First-in-human studies are often expected to provide robust ECG evaluation, including PR interval.
On the other hand, if safety pharmacology studies are equivocal or suggestive of drug-induced PR interval prolongation or AVB or there is relevant concern based on structural pharmacologic drug class considerations, enrolling subjects with PR intervals ≤ 200 to 220 ms, without any evidence of second-degree AVB, might be advisable. There is increasing interest in making more effective use of high-quality early-phase ECG data to make earlier and more definitive assessments of drug exposure-response (and PK/PD modeling) and time course of effect characterizations of ECG effects, including PR, QRS, and QT/QTc intervals. Consequently, in early-phase clinical studies, subjects with more than mild first-degree AVB (200–220 ms) or type I second-degree block at rest on screening ECGs might not be best suited for fully assessing potential drug effects. For drugs with potential clinical effects, additional intensive CV monitoring, such as with real-time cardiac telemetry and Holter monitoring, can be added as warranted, to ensure volunteers' safety, profile relevant drug effects, and clear exposures intended for less monitored settings.
Patients Exposure margins in ambulatory patients are usually maintained below those found to be safe in healthy volunteers. The intensity of the clinical and ECG monitoring schedules should be guided by PK characteristics, administered comedications, associated morbidity, clinical feasibility, and possible CV conditions.
Exploring differences in relevant responses between healthy subjects and patient populations early in development can be very informative. However, individuals with relatively high probability of having underlying relevant CV conditions, with AVB, or taking concomitant medications that can cause PR interval prolongation are probably at higher risk for adverse events. Such patients could be excluded from clinical trials with investigational drugs that may adversely affect AV conduction until relevant exposure risk has been better profiled in healthy subjects, or in definitive CV studies. If definitive CV studies are not feasible, careful screening may be necessary to exclude subjects with moderate PR interval prolongation (eg, >220–240 ms), higher-grade AVB, or documented history of relevant symptoms (eg, syncope). It is important in patient trials, as well as in healthy volunteer studies, to exclude subjects who manifest accessory pathways, for example, ventricular preexcitation (δ waves).
Definitive ECG Studies With the possible exception of small-molecule oncology drugs and monoclonal antibodies, definitive ECG studies, or thorough QT/QTc (ECG) studies, are almost always required before expanded patient exposure in phase III clinical trials and provide robust ECG-based intervals analyses. Generally, the analyses from definitive ECG studies include the following:
Central tendency analysis: for example, absolute mean PR interval measurements with 95% confidence interval (CI), baseline-adjusted PR interval with 90% CI, and placebo- and baseline-adjusted PR interval with 90% CI
Exposure-response assessment: when analysis of central tendency or categorical analysis of outliers raises cause for concern
Categorical outlier analysis: the number and proportion of subjects with PR interval values >200, 220, and 240 ms. Categorical values for analysis should take into consideration inclusion and exclusion criteria, such as inclusion of subjects/patients with baseline values as high as 220 ms. If outliers are detected, a follow-up categorical analysis of the number and proportion of outlier ECG values will often be needed as well as the number and proportion of outliers by time point in addition to the total number and proportion outliers over the observation period.
Narratives provided for any subjects with AVB, especially higher-grade AVB
Relevant ECG morphologic assessment to inform assessment of subjects with AVB
If these definitive CV studies identify clinically significant AV conduction risks, additional expanded clinical monitoring will likely need to be implemented in at-risk patients during subsequent phase III studies. In this case, it may be helpful to also include informative PK sparse sampling that enables exposure-response evaluation of AVB-related adverse outcomes.
Discontinuation of Subjects Dosing During Study Conduct Discontinuation decisions are modulated by the overall risk/benefit assessment and will often reflect the incomplete understanding of the risk posed by drug-induced AVB at the individual subject level. The following points can be considered when selecting criteria to define discontinuation relevant to AVB issues:
A.At the individual subject level
Absolute PR interval prolongation beyond a predefined threshold (eg, >240 or >260 ms)
Relative PR interval change from baseline (eg, >25%)
Second-degree AVB type 2 or higher
Symptoms and signs of decreased cardiac output
B.At the study cohort level
Serious or severe AVB relevant adverse events in 1 or more subjects
Mean marked PR interval prolongation or change from baseline
Clinically significant increase in incidence of AVB or adverse events suggestive of decreased cardiac output
It is important to note that many subjects with AVB in early-phase studies will not have symptoms from the AVB, and if risk/benefit is appropriate, higher values for drug discontinuation may be warranted with ECG and subject monitoring and risk mitigation. For example, in many cases, subjects become relatively hypovolemic and, after prolonged recumbency and repeated blood draws and procedures, are more prone to vagal-mediated episodes that may include orthostatic hypotension, bradyarrhythmias, and various degrees of AVB, which can be minimized by keeping subjects hydrated and recumbent.
Event Management During Clinical Trial Conduct
Clinically significant PR interval prolongation and AVB observed during clinical events should be managed adequately to ensure subjects' safety. Individuals affected should be evaluated by an experienced physician. Blood sampling closest to the time of the event provides drug exposures, and clinical safety laboratory tests may rule out relevant undiagnosed conditions, for example, hypothyroidism. Additional history could uncover any unknown illnesses and medications intake that can affect the autonomic rhythm control, such as sympatholytic or vagomimetic drugs (eg, ophthalmic treatments are occasionally overlooked). This extensive evaluation will be useful for clinical study reports narratives requested by sponsor safety analysts and regulatory agencies.
Premarketing or Postmarketing Analysis of Adverse Experience
The following adverse events probably represent outcomes potentially related to AVB and hence are informative to analyze when performing premarketing analyses of clinical trial data or postmarketing surveillance:
Heart block
Pacemaker implantation
Atrial flutter/fibrillation
Progression of CAD
Clinically significant bradycardia
Sudden death
Symptoms of decreased cardiac output or decreased exercise tolerance
Presyncope or syncope
Program Wide Profiling and Analysis of PR Interval Prolongation
Evaluating treatment-emergent PR prolongation or AVB is guided by the expected variability of these end points and prognosis of findings in excess of that variability. The use of 24-hour Holter monitoring for arrhythmic screening on selected study days can be a useful strategy used to identify AVB during initial dosing and steady-state treatment with investigational drugs that may affect AV conduction. The pregabalin (Lyrica, Pfizer, New York, NY) FDA New Drug Application review experience exemplifies an approach to evaluate results of a clinical development program, as profiled below:
Mean PR interval increase (placebo adjusted) supported by exposure-response analysis
Incidence of advanced AVB on active drug compared with placebo, investigating dose dependency and high-risk subgroup analysis (see below)
Outlier analysis comparing incidence on active drug and on placebo, and exposure dependency if any for the following subjects:
Absolute PR interval >200 to 220 ms
PR interval increase from baseline >25%
High-risk subgroup analysis evaluating placebo-adjusted PR prolongation as well as incidence of second- and third-degree AVB for the following subgroups:
Subjects with baseline PR interval >200 to 220 ms
Subjects on concomitant medications known to prolong PR interval, or cause AVB (mitigating any attribution bias)
Additional analyses can include relevant adverse event and serious adverse event analysis.
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