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Trough:Peak Ratio of Antihypertensive Medications and Treatment of Hypertension

Summary:

  • The treatment of 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 being able to do so with medications that can be administered once-a-day.
  • The Food and Drug Administration (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%.
  • 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 criteria for maintaining adequate blood pressure lowering for a period of 24 hours and thus could be approved for once-a-day dosing.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed:
August 2015

Explanation

  • The 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 cardiovascular complications.3-5 

    The 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 

    The 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 administered)
    • 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 dosing. 

    A 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. 

    A 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). 

    Regardless, 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.

    References:

    1. DeVore AD, Sorrentino M, Arnsdorf MF et al.  Predictors of hypertension control in a diverse general cardiology practice.  J Clin Hypertens 2010;12:570-7.  
    2. 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. 
    3. 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.  
    4. 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.  
    5. Frattola A, Parati G, Cuspidi C et al.  Prognostic value of 24 h BP variability. J Hypertens 1993;11:1133-7.  
    6. 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.  
    7. Mancia G, Parati G.  The role of blood pressure variability in end-organ damage.  J Hypertens  2003;21:S17-23.  
    8. Zannad F, Radauceanu A, Parati G et al.  Trough-to-peak ratio, smoothness index and morning-to-evening ratio: why, which and when?  J Hypertens 2003;21:851-4.

MESH Terms & Keywords

  • Trough Peak Ratio for Hypertension Treatment