*In this panel, a typical time profile of systolic blood pressure (SBP) is displayed.*
Blood pressure, like other human biological markers, is characterized by predictable changes during the 24 hours, for the most part in synchrony with the rest-activity cycle . This circadian variation represents the influence of:
- intrinsic factors: gender, autonomic nervous system tone, vasoactive hormones, and hematologic and renal variables,
- extrinsic factors: sleep/wake routine, physical activity, ambient temperature/humidity, emotional state, alcohol or caffeine consumption, and of course, medical treatment - in treated patients.
Some specific features of the 24h BP pattern are linked to the triggering of cardiac and cerebrovascular events. The day/night variation of blood pressure (BP) has been used to classify patients into nocturnal ‘dippers’ (≥10% drop in BP overnight – 23:00 to 07:00) and ‘non-dippers’. It has been shown that non-dippers, as well as patients with increased morning surge, are at increased risk for serious cardiovascular adverse events .
*Click on the button to get new SBP profiles.*
The purpose of this animation is to give you a sense of the differences in BP time profiles between patients.
Despite the circadian rhythm of BP being typically described as sinusoidal, a large inter-subject variability is usually observed in clinical setting. Each patient is following a different time profile, with her/his own mean SBP level (MESOR), amplitude, and peaks or nadirs. To identify the sources of variability in the data and quantify them, we use statistical models with random effects.
*Click on a check-box to add or remove data and model corresponding to each dose group.*
In the below figure, we display the SBP data observed at end-of-study in patients who have received a medical treatment, either at dose 0.4 mg, 2 mg, 10 mg, or placebo once daily for 12 weeks. The observed data are plotted as dots, and the best-fitting model to describe these data is plotted as a plain curve.
As you can see, as the dose increases, the MESOR decreases; these patients receive an anti-hypertensive treatment :). The SBP of each participant was measured every 15 minutes over 24h at the occasion of each visit to the physician during the trial.
0.4 mg qd
2 mg qd
10 mg qd
The model we use to describe the data consists in a series of harmonic terms :
The number of harmonic, K, is usually equal to 2 or 3 depending on the clinical setting, amount and quality of data.
This type of model can be easily implemented in any statistical programming environment e.g. R/nlme, NONMEM, Phoenix/nlme, SAS/NLMIXED.
*Experiment by yourself:*
- mouse over the dose-MESOR (figure on the right)
- change the model parameter values (in the control panel)
In early development, a major objective of the analysis BP data is to define the dose-concentration-effect relationship for the drug, in order to guide dosage form development (e.g. extended-release vs immediate-release) and to define the dosing regimen for the pivotal phase III trials.
The effect of drugs on phase shifts (i.e. changes in peak and nadir locations on the x-axis) has rarely been modeled, but to study chronotherapy . More frequent are the cases where the drug effect – i.e. dose-response – is factored in the BP model as a covariate influencing the MESOR.
*Use your mouse to get your head around the radial plot (on the right)*
In this last panel, two graphical representations of the same phenomenon are presented. One the left-hand side, the ‘conventional’ plot displays the SBP data using Cartesian coordinates. On the right-hand side, the ‘radial’ plot (a.k.a. polar plot) displays the same data using polar coordinates. Many criticisms have been formulated towards polar plots . However, there are conditions under which this format may be acceptable; depiction of circadian data is one as it mirrors the cognitive image we have of a clock. In addition, a (24h) loop can be displayed in a radial plot; something a Cartesian plot cannot do.