management and overall control of hypertension can be influenced by a number of
different factors, one of which includes the antihypertensive drug therapy
being used. It is well known that one-time blood pressure readings in the
clinic or acute care settings are not an accurate reflection of the average
blood pressure throughout the day.1-3 This is why ambulatory blood
pressure monitoring has gained greater use over the years.3-6 This is
relevant because the average blood pressure throughout the day is known to be
correlated with the risk for developing target organ damage and future
pharmacotherapeutic approach to treating hypertension has evolved over time to
include medications that are not only effective at maintaining reductions in
average blood pressure readings over a 24 hour period, but are able to do so
with medications that can be administered once-a-day. Oral once-a-day
dosage formulations are considered by most clinicians as being ideal for the
purpose of patient adherence and acceptance. However, due to different
pharmacological and biological effects of antihypertensive medications, not all
antihypertensive medications and/or dosage formulations allow for oral once-a-day
dosing. This is where the trough:peak ratio was originally proposed by
the Food and Drug Administration (FDA).6-8
FDA proposed that before an antihypertensive medication could be approved for
once-a-day dosing it would have to have a trough:peak ratio value of greater
than 50%.8 This is based on the medication's pharmacokinetic profile in
relation to the blood pressure at various times throughout a 24 hour
period. The trough:peak ratio is basically assessed by the following:
- The patient's baseline blood pressure is determined (before any medication is
- The antihypertensive medication is then given to the patient
and blood pressures are then assessed using ambulatory blood pressure readings
over 24 hours
- Determination of the "peak" blood pressure lowering
effect as compared to baseline in that 24 hour time frame (or said another way,
the greatest degree of blood pressure lowering when compared to the baseline
blood pressure for that medication)
- Determination the "trough"
or degree of blood pressure lowering compared to baseline that remained at the
end of the 24 hour period (i.e., the "trough" in this situation is
the drug concentration remaining in the blood right before the next dose would
normally be given).
If the degree of blood pressure lowering at the end
of the 24-hour period (i.e., suspected to be the drug's "trough"
effect) is at least 50% of the peak blood pressure lowering effect, then that
antihypertensive medication (for that dosage formulation) has meet the FDA's
criteria for maintaining adequate blood pressure lowering for a period of 24
hours and thus could be approved for once-a-day dosing. For example, if
the average peak blood pressure lowering effect of drug A was 10 mmHg and if
the average trough blood pressure lowering effect at the end of that 24 hour
time period was 6 mmHg, then the trough:peak ratio would be >50%, because
6/10 equals 0.6 or 60%. Said another way, 60% of the peak blood pressure
lowering by drug A still remained at the end of the 24 hour period.
Therefore, in this example Drug A would be given approval for once-a-day
trough:peak ratio of >50%, also means that the antihypertensive medication
allows for once-a-day dosing without causing pronounced reductions in blood
pressure that is sometimes seen with short or rapid acting antihypertensive
agents. Medications that would cause a pronounced drop in blood pressure
that returned back to baseline in less than 24 hours would have a low
trough:peak ratio. This is important since many short or rapid acting
medications are also known to cause more side effects and reduced organ
perfusion, thereby resulting in orthostasis, rebound tachycardia, increase
oxygen, and upregulation of counter neurohormonal systems.
few final points are also important for clinicians to keep in mind regarding
this topic. The first includes the observation that different
antihypertensive medications not only have different pharmacological effects,
but are also known to vary in their elimination and biological half-lives.8
As such, a medication's concentration at the trough period could be negligible,
but the biologic effect from that medication is still exerting its effect on
the blood pressure. The second includes the observation that blood
pressure readings are influenced by a number of factors, some of which include
the technique or mechanism of measurement and various behavior related factors
(e.g., smoking, caffeine intake, stress, etc.). These are known to be
problematic for the accurate interpretation of the trough:peak ratio if not
accounted for and have resulted in bias or poor reproducibility on occassion.8
This is why some clinicians advocate the use of the smoothness index, which
accounts for some of these limitations by allowing for a more comprehensive
assessment of the information collected over the 24 hour time period rather
than a few points in time.8 The third and last includes the observation
that medications with a trough:peak ratio less than 50% should be dosed more
frequently throughout the day in order to maintain adequate blood pressure
lowering throughout a 24 hour period of time. A good example of this is
oral immediate release formulation clonidine (an alpha-2 agonist) or captopril
(an ACE inhibitor).
the use of established antihypertensive agents with the ability to be dosed
once-a-day should be used in the management of hypertension when
available. While there are a few limitations to the trough:peak ratio, it
is one parameter that can guide the clinician to know which antihypertensive
medication to use in a particular patient.
- DeVore AD, Sorrentino M, Arnsdorf MF et al. Predictors of
hypertension control in a diverse general cardiology practice. J Clin
- Majahalme S, Turjanmaa V, Weder AB et al. Blood pressure level
and variability in the prediction of blood pressure after 5-year follow
up. Hypertension 1996;28:725-31.
- Verdecchia P, Clement D, Fagard R et al. Blood pressure
monitoring. Task force III: Target-organ damage, morbidity and
mortality. Blood Press Monit 1999;4:303-17.
- Parati G, Pomidossi G, Albini F et al. Relationship of 24-hour
blood pressure mean and variability to severity of target-organ damage
in hypertension. J Hypertens 1987;5:93-8.
- Frattola A, Parati G, Cuspidi C et al. Prognostic value of 24 h BP variability. J Hypertens 1993;11:1133-7.
- Staessen JA, Bieniaszewski L, Buntinx F et al. The
trough-to-peak ratio as an instrument to evaluate antihypertensive
drugs. The APTH Investigators. Ambulatory Blood Pressure and Treatment
of Hypertension Trial. Hypertension 1995;26:942-9.
- Mancia G, Parati G. The role of blood pressure variability in end-organ damage. J Hypertens 2003;21:S17-23.
- Zannad F, Radauceanu A, Parati G et al. Trough-to-peak ratio,
smoothness index and morning-to-evening ratio: why, which and when? J