What is the Rationale for Treating Elevated BP Initially with Combination Therapy?

Thomas D. Giles, MD
Published Online: Monday, September 1, 2003
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Although the proportion of patients who achieve blood pressure (BP) control has increased in the past quarter century, it remains low at only 34%, observed Thomas D. Giles,MD.

To bring more patients to goal, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) (Chobanian AV, et al. JAMA. 2003;289:2560-2571) recommends that patients initially >= 20/10 mm Hg beyond target should be started on 2 medications, "either as separate prescriptions or as fixed-dose combinations."

JNC 7 also raised the bar on ideal treatment goals by reducing the upper threshold for "normal" BP to < 120/< 80 mm Hg, compared with < 130/< 85 in JNC 6. Cardiovascular (CV) risk begins to rise when BP reaches 115/75 mm Hg and doubles with every increment of 20 mm Hg systolic blood pressure (SBP) and 10 mm diastolic blood pressure, notes the updated report.

"To clinicians, that means that the level of SBP is a test of the CV  system.When SBP rises above 115 mm Hg, it is telling us something we shouldn?t ignore, and patients shouldn?t ignore,"Dr. Giles said.

Drug therapy, according to the algorithm, should be started in patients with BP >= 140/90 mm Hg, or >= 130/80 mm Hg in those with diabetes or chronic kidney disease.Those with uncomplicated hypertension should usually start out with a thiazide-type diuretic, the algorithm says, possibly in addition to an angiotensin- converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), betablocker, or calcium-channel blocker (CCB). Starting out with multiple drugs "may increase the likelihood of achieving the BP goal in a more timely fashion," with caution indicated in patients at risk for orthostatic hypotension.

Patients who do not reach goal BP should have dosages titrated upward or additional agents added. "The guidelines say that ?failure to titrate or combine medications, despite knowing the patient is not at goal BP, represents clinical inertia and must be overcome?? a fairly powerful statement," Dr. Giles said. He noted that randomized studies suggest that patients could need anywhere from 2.5 to 4 drugs to achieve target BP.

Some drug-class combinations are particularly effective as initial therapy, according to Dr. Giles. "ACE inhibitors or ARBs, as well as beta-blockers, work well with CCBs or with diuretics." Less effective combinations, he noted, might include a beta-blocker plus an ACE inhibitor or ARB.

Drugs that block the renin-angiotensin system (RAS) may have an edge as initial therapy in that they are known to attenuate hypertensive damage to the heart, kidneys, and other target organs, Dr. Giles observed. "Since a lot of patients will require more than 2 drugs, we should be looking for ways to combine drugs that are RAS-active.The potential advantages are better efficacy and perhaps better outcomes."

That view was supported by the recent Safety of Lotrel and Amlodipine in a Comparative Efficacy (SOLACE) trial, in which 364 patients with hypertension were randomized to receive amlodipine with or without benazepril (Neutel JM,Weir MR. Am J Hypertens. 2003;16:196A). The starting dosage was 5/20 mg/day of amlodipine/benazepril or 5 mg/day of amlodipine. Patients who achieved a target BP of ?? 130/85 mm Hg at week 2 continued at this dose level; for those who did not, the dose was titrated to 10/20 mg/day of amlodipine/benazepril or 10 mg/day of amlodipine.

By the 12th week of therapy, Dr.Giles noted, 53.9% of patients taking the CCB alone and 74.2% of those on combination therapy (P < .0001) had reached goal BP. The average decrease in SBP was significantly greater with the combination of amlodipine and benazepril in the population overall. This was also illustrated in a subset of patients with a baseline SBP >= 180 mm/Hg (Figure 1).

Figure 1

A fixed-dose combination regimen might allow lower dosages of each agent as compared with what would be used in titrated monotherapy. This could reduce the risk of adverse effects and patient noncompliance, Dr. Giles said.



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