Not all antihypertensive drugs provide full 24-hour coverage. This article describes methods for evaluating the duration of action of antihypertensive compounds and why good 24-hour blood pressure control is important in routine family practice.

Encouraging long-term adherence to antihypertensive treatment was the main theme of the 2006 Canadian Hypertension Education Program. Interesting how history repeats itself. Compliance with drug therapy actually got its start with the treatment of hypertension. Thirty years ago, a typical patient might be taking methyldopa 500 mg three times a day, hydralazine 50 mg four times daily and hydrochlorothiazide 100 mg once daily, together with eight potassium tablets. Not surprising that some patients found it difficult to follow such complex therapeutic regimens.

Today, the standard antihypertensive drug is given once daily. Few companies would consider marketing a drug that requires more frequent dosing intervals. How rigorous are the standards for approving once-daily therapy and do current drugs meet these standards?

Measuring BP in the office
Until recently, one only needed to demonstrate a significant reduction in BP prior to the next dose in order to have an antihypertensive drug approved for use in clinical practice. Typically, with a once-daily agent, BP was recorded in the morning, prior to the next dose. Providing the diastolic BP was at least 5 mmHg lower than with placebo, the drug was given approval by regulatory authorities. The trend away from multiple daily dosing led some companies to “over-dose” patients, e.g. giving drug X 100 mg twice daily instead of 50 mg three times daily in order to prolong the duration of action, thus reducing dosing frequency while still achieving a reduction in BP at the end of the longer dosing interval. This development sparked interest in what might be happening to the BP during the time of the drug’s peak effect. This concern led regulatory authorities to become interested in the maximum reduction in BP (peak) compared with the reduction in BP prior to the next dose (trough). Several methods were then developed to obtain a measure of the time-course of BP reduction based on readings in either the office or research unit setting.

The simplest method to evaluate once- versus twice-daily dosing was to measure BP in the morning with each of these regimens by recording “trough” BP. If the mean BP value was the same 24 hours after a full dose and 12 hours after the same dose given twice daily, then the drug was deemed to be suitable for once-daily administration.

A more sophisticated method involved having patients remain in the office or research unit for eight to 12 hours and then returning at 24 hours to obtain both the maximum reduction in BP and the trough effect. Some investigators used this approach to calculate a trough to peak ratio (TPR) for each drug. TPR as a concept may have made sense in theory but it did not work out so well when applied to real patients with variable BP readings. The arrival of 24-hour ambulatory BP monitoring (ABPM) soon superceded studies done in the office.

Twenty-four hour ABPM involves the automated measurement of BP several times an hour during usual daily activities and less frequently during sleep. Several methods evolved to demonstrate the duration of action of antihypertensive drugs using this technology, including:

• descriptive display of changes in BP after drug versus placebo;

• estimation of trough-to-peak ratio;

• mean daytime, evening and nighttime readings after dosing; and

• missed-dose technique for reduction in BP beyond 24 hours.

The simplest method for visualizing a drug’s effect on BP over a standard dosing interval (e.g. 24 hours) is to look at a graphic display of mean hourly BP over 24 hours after drug administration, usually after several weeks of therapy (see graph 1). As can be seen from the example, telmisartan 80 mg daily reduced both systolic and diastolic BP over 24 hours, whereas ramipril 10 mg daily exerted a more pronounced effect between three and nine hours, with subsequent loss of BP control.

It did not take long for some investigators to apply the concept of TPR to data derived from ambulatory BP recordings. From the example noted above, one could estimate a maximum reduction in diastolic BP for telmisartan of 11 mmHg between seven and nine hours after dosing compared with 9 mmHg at the end of the dosing interval, giving a TPR of 9/11 (82%).

In contrast, the peak effect of ramipril was close to 9 mmHg with only half of this effect being present at 24 hours, giving a TPR of about 50%. Once again, converting changes in BP over 24 hours to an arithmetic ratio worked well in theory but became subject to statistical manipulation when some patients ended up with greater reductions in BP at trough than at peak or no reduction in BP at trough.

Another approach to using 24-hour ABPM to assess duration of antihypertensive effect is to calculate mean daytime, evening and nighttime values. In one study, nifedipine was compared with enalapril, each given once daily. Both drugs reduced BP during daytime hours significantly but only nifedipine had a persistent antihypertensive effect over 24 hours, whereas enalapril was less effective during the nighttime period and especially before the next dose was to be given at 24 hours (see graph 2).

Substitution of a placebo for active drug allows one to determine the duration of antihypertensive effect over longer periods, e.g., 48 to 72 hours. One study (Lacourcière Y, et al.) examined the duration of action of telmisartan 80 mg during a 48-hour period in 437 hypertensive patients. Placebo was substituted for active therapy (missed-dose design) on the second day and the BP was followed for the period 24 to 48 hours after the active medication had been taken. The result was significant reductions in both systolic and diastolic BP with telmisartan during the entire 48-hour period after medication was taken (see graph 3).

A more complex missed-dose design was used to demonstrate the duration of action of a combination of perindopril 4 mg plus indapamide 1.25 mg for up to 72 hours after dosing (Myers MG, Leenen FH). Data from mean changes in 24-hour blood pressure after dosing at baseline (zero to 24 hours), after one missed dose (24 to 48 hours) and after two missed doses (48 to 72 hours) show that the perindopril-indapamide combination reduces blood pressure for up to 72 hours (see graph 4). Since combination therapy is being used more often in clinical practice, it is important to know the duration of the antihypertensive effect when more than one drug is being prescribed.

Regulatory authorities still like to see the reduction in office BP at 24 hours compared with placebo as part of a new drug submission. However, ABPM has become an important part of the assessment of new antihypertensive drugs using different approaches to data analysis for comparative studies with placebo or other agents.

Compliance and coverage
Hypertension is a common problem that remains woefully under-addressed, in no small part because of compliance issues. Even the most effective treatment won’t work unless it is taken as prescribed. We know that once-a-day medications increase compliance, and should be used wherever possible. But do all once-daily antihypertensive medications provide true 24-hour-plus coverage? This is of particular concern to family physicians when they are choosing treatment for their hypertensive patients, especially those suspected of poor compliance, since 24-hour-plus antihypertensive coverage could save their lives.

Our expectations of hypertension treatment effectiveness are based on presumed patient compliance, despite our awareness that compliance is so poor patients who take only 80% of a prescribed medication are considered compliant. What happens to patients who are compliant only 50% or 60% of the time? Given the circadian-related morning surge in blood pressure, it’s no coincidence that the majority of cardiovascular events occur in the morning, when a medication’s antihypertensive effect is likely at its lowest (trough) level.

Consider this common scenario: The patient who gets up at 5:30 a.m. every day, Monday to Friday, takes his BP medications and goes to work. What happens on the weekend, when that individual sleeps in until 8:30 or 9 a.m., and takes his medications then? We’re already expecting the medication to provide 28 or 29 hours of antihypertensive effect and the patient hasn’t even missed a dose. If we are to protect such patients, as well as those who are noncompliant, we need convincing evidence that a medication provides true 24-hour-plus antihypertensive coverage.

Providing this coverage is vital in patients who are known, or likely to be, noncompliant. When a patient reports good home BP readings to the family physician, and values are consistently high in the office, there is a strong rationale for 24-hour ambulatory blood pressure monitoring. If this is difficult to access, a reasonable substitute is to use home BP monitoring, which provides multiple readings over a period of days or weeks taken outside the office setting. The use of validated home BP recorders should be encouraged. Such devices can be identified by looking for the endorsement of the Canadian Hypertension Society on the packaging. Alternatively, family doctors can use the validated, automated BpTRU device to obtain readings in the office, which minimizes factors contributing to a white-coat response. The BpTRU allows one to record a patient’s BP with five readings taken over a period of five to 10 minutes without anyone being present in the examining room. Patients can then be directed to the Canadian Hypertension Society website (www.hypertension.ca) for a list of accredited monitors.

Choosing a medication
In these compliance-focused times, many medications are marketed as single daily-dose drugs; however, the extent to which their effects extend for 24 hours and beyond varies. Missed-dose data are the most important indicators to look to for assurance that a medication will provide at least 24-hour protection. Missed-dose studies can help identify intra-class differences in the duration of effect of once-daily medications. For instance, comparison of the antihypertensive effects of telmisartan versus valsartan (Leenen FH, et al.) showed telmisartan provided more sustained BP control, especially at the end of the dosing period, and was statistically superior in terms of missed dose data.

Given that many patients require more than one antihypertensive medication in order to reach their target blood pressure, combination treatments are already in widespread use. However, not all antihypertensive combinations are ideal. Physicians must consider which combinations can provide the optimal risk-benefit balance for each individual patient. This involves a thorough assessment of the patient’s comorbidities and cardiovascular risk factors. For example, hypertensive patients with target organ damage may benefit from specific agents such as drugs that block the renin-angiotensin system or beta-receptor blocking agents. Low-dose thiazide diuretic therapy is often used as an adjunct to attain a normal BP.

Family physicians need to be open to new developments in antihypertensive pharmacotherapy in order to make the best choices for hypertensive patients. The selection of a medication should be based not only on choosing a favourable class of antihypertensive agent, but also on prescribing the best drug in that class on the basis of its solid scientific evidence and its pharmacological properties. In our experience, we have seen that by prescribing a medication or combination that provides true 24-hour antihypertensive protection, and giving more of our time and attention to barriers to good compliance, we can help our patients achieve greater than 90% compliance, and 70% can reach their BP target. We can do better. Ü•

References

Myers MG. Methods for evaluating the duration of action of once-daily antihypertensive therapy. Blood Press Monit. 2003 Aug;8(4):161-3.

Lacourcière Y, Neutel JM, Davidai G, Koval S. A multicenter, 14-week study of telmisartan and ramipril in patients with mild-to-moderate hypertension using ambulatory blood pressure monitoring. Am J Hypertens. 2006 Jan;19(1):104-12.

Leenen FH, Myers MG, Joyner CD, Toal CB. Differential effects of once-daily antihypertensive drugs on blood pressure, left ventricular mass and sympathetic activity: Nifedipine-GITS versus felodipine-ER versus enalapril. Can J Cardiol. 2002 Dec;18(12):1285-93.

Lacourcière Y, Krzesinski JM, White WB, et al. Sustained antihypertensive activity of telmisartan compared with valsartan. Blood Press Monit. 2004 Aug;9(4):203-10.

Myers MG, Leenen FH; General Practice Research Group. The impact of one or two missed doses on the duration of action of combined perindopril and indapamide. J Hum Hypertens. 2007 Jan;21(1):86-93.

Leenen FH, Wilson TW, Bolli P, et al. Patterns of compliance with once versus twice daily antihypertensive drug therapy in primary care: A randomized clinical trial using electronic monitoring. Can J Cardiol. 1997 Oct;13(10):914-20.