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P T. 2010 June; 35(6): 336, 343-344.
PMCID: PMC2888546

American Society of Hypertension

25th Annual Scientific Meeting and Exposition

American Society of Hypertension

Angiotensin-Receptor Blocker Combinations

Among the 2,908 registrants at the 2010 Annual Scientific Meeting and Exposition of the American Society of Hypertension (ASH) in New York City from May 1 to 4, more than half were from countries outside the U.S. (1,580) and 456 were hypertension specialists. Key presentations, reviewed here, include a study of a low-dose combination of agents for weight loss and blood pressure reduction and three studies of angiotensin-receptor blockers in combination with other agents.

Controlled-Release Phentermine/Topiramate (Qnexa) Improves Blood Pressure, Weight, and Glycemic Control

  • Suzanne Oparil, MD, University of Alabama, Birmingham, Alabama

Phentermine/topiramate controlled release (PHEN/TPM CR) combines PHEN (e.g., Adipex-P, Gate), an agent approved in 1959 as a short-term adjunct to diet and exercise that stimulates high levels of catecholamines, and TPM (Topamax, Ortho-McNeil), approved in 1996 for seizure disorders and migraine. Once-daily, low-dose PHEN may suppress appetite and increase satiety, and TPM CR is noted to have favorable effects on weight, glycemic control, and blood pressure (BP) after 28 weeks. The combination has been approved as Qnexa (Vivus).

Both PHEN and TPM, used individually, were associated with adverse effects (AEs) at their recommended doses. When combined at lower doses in a once-daily formulation, however, they produced significant weight loss and reductions in hypertension in obese and overweight individuals, according to an integrated analysis of three pivotal phase 3 trials (EQUATE, EQUIP, and CONQUER).

Dr. Oparil noted that the prevalence of overweight and obese adults with a body mass index (BMI) of 25 kg/m2 or higher in the U.S. is 68% (NHANES 2007–2008) and increasing. At the same time, diet and exercise often achieve only marginal weight loss, and safety and tolerability concerns often impede the long-term success of approved weight-loss agents.

In the three-trial analysis, investigators aimed to evaluate weight loss and BP changes over 28 weeks in overweight and obese subjects and to confirm maintenance of any changes through 56 weeks. The trial included 1,580 patients receiving placebo, 234 receiving PHEN/TPM CR at 3.75 mg/23 mg, 591 at PHEN/TPM CR 7.5 mg/46 mg, and 1,582 at PHEN/TPM CR 15 mg/92 mg. Mean BMI for the four groups ranged from 36.3 to 42.5 kg/m2.

The primary endpoint was the percentage of weight loss from baseline to week 28 for the three trials combined. Patients in the placebo group were actively counseled on lifestyle modifications, diet, and exercise.

At 28 weeks, rates of weight loss were 1.9% for placebo and 5.1%, 8%, and 9.9%, respectively, for the increasing PHEN/TPM CR doses (P < 0.0001 vs. placebo for all PHEN/TPM CR doses). At 56 weeks, rates of weight loss followed a similar pattern: 1.5% for placebo and 4.7%, 8.2%, and 10.4% for the increasing PHEN/TPM CR doses (P < 0.0001 for all).

Changes in systolic BP were −3.06 mm Hg for placebo and −5.13, −6.77, and −6.51 mm Hg, respectively, for the increasing PHEN/TPM CR doses (P < 0.05 vs. placebo for all PHEN/TPM CR doses). Changes in diastolic BP were −1.29 mm Hg for placebo and −1.64, −3.05, and −2.82 mm Hg, respectively, for PHEN/TPM CR doses (P < 0.05 for the two higher PHEN/TPM CR doses).

Most AEs were mild or moderate in severity. The discontinuation rates for AEs were 8.5% for placebo, 11.7% for PHEN/TPM CR 3.75 mg/23 mg, 11.6% for PHEN/TPM CR 7.5 mg/46 mg, and 17.5% for PHEN/TPM CR 15 mg/92 mg.

“PHEN/TPM CR is a novel, oral, low-dose controlled release treatment that can lead to significant weight reduction and may address common obesity-related comorbidities such as hypertension,” Dr. Oparil concluded.

Blood Pressure Control with Amlodipine (Norvasc) plus Olmesartan (Benicar) with or without Hydrochlorothiazide: The BP CRUSH Trial

  • Joel M. Neutel, MD, Professor of Medicine, University of California, Irvine, Calif.

A study of patients whose hypertension had not been controlled with previous monotherapy showed that switching to a dual-titration regimen with the calcium-channel blocker amlodipine besylate (AML, Norvasc, Pfizer) and the angiotensin-receptor blocker (ARB) olmesartan medoxomil (OM, Benicar, Sankyo Pharma) brought 75% of patients to systolic BP goals of below 140 mm Hg and below 130 mm Hg in diabetic patients by week 12.

BP CRUSH (Blood Pressure Control in All Subgroups with Hypertension), according to Dr. Neutel, examined clinical inertia, in that it included a population representative of the 50% of treated hypertensive patients whose BP is inadequately controlled with monotherapy. The term clinical inertia implies that initiation and/or intensification of medical therapy have been delayed.

“There are so many obstacles in clinical practice to getting patients to goal—their resistance to taking multiple pills, their concerns over side effects, cost, safety—and it ends up with inadequate blood pressure control,” Dr. Neutel said in an interview.

He added, “We did a simple clinical switch. We took them from one drug once a day to a combination of two drugs in one pill once a day.”

BP CRUSH included 999 nonresponders to antihypertensive monotherapy. Uncontrolled hypertension was defined as a systolic BP between 140 and 180 mm Hg and a diastolic BP lower than 110 mm Hg and between 130 and 180 mm Hg for diabetic patients. Approximately 145 sites were included (105 in the U.S., 40 in South Africa).

Among enrolled groups with 100 or more individuals were the elderly (65 years of age or older), African-Americans/Blacks, Hispanics, Asians, and patients with type-2 diabetes, metabolic syndrome, and obesity. (Obesity was defined as a BMI of 30 kg/m2 or greater.) Mean baseline systolic BP/diastolic BP for the total cohort was 153.7/91.9 mm Hg, respectively.

Patients received AML/OM 5/20 mg, and the dose was titrated upward, as needed, to AML/OM 5/40 mg at week 4 and to AML/OM 10/40 mg at week 8. A diuretic, hydrochlorothiazide (HCTZ) 12.5 mg, was added, as needed, at week 12, and HCTZ 25 mg was added at week 16.

The primary endpoint of BP CRUSH was the proportion of patients achieving a cuff systolic BP of below 140 mm Hg, or below 130 mm Hg for patients with diabetes, after 12 weeks.

The mean change from baseline in systolic BP was −14.2 mm Hg at week 4 with AML/OM 5/20 mg. The reduction increased at each four-week assessment, reaching −25.1 mm Hg at week 20.

By week 12, 75.8% of subjects had achieved the systolic BP goal in at least one measurement (80.1% of those without diabetes and 57.9% with diabetes). The diastolic BP goal (below 90 mm Hg and below 80 mm Hg for those with diabetes) was reached by 84.3% of subjects (89.2% and 63.7%, respectively, of those with or without diabetes). At week 20, 90.3% of patients had achieved their goal at any point. The combination of AML/OM, with or without HCTZ, was well tolerated.

In an interview, Dr. Neutel said, “This helps us to overcome the many clinical barriers and get patients to goal.”

He added that in his own practice, because of calcium-channel blocker endothelial benefits and the adverse metabolic effects of HCTZ, he is leaning toward the angiotensin/calcium-channel blocker combination.

Olmesartan plus Hydrochlorothiazide (Benicar HCT) plus Amlodipine (Norvasc) For Hypertension: The TRINITY Study

  • Suzanne Oparil, MD, University of Alabama, Birmingham, Alabama

Treatment of moderate-to-severe hypertension with olmesartan medoxomil (OM) plus HCTZ (Benicar HCT), combined with amlodipine besylate (AML) (Norvasc), resulted in significantly greater mean reductions in diastolic and systolic BP values than corresponding therapy with two-drug combinations.

“There is a need to have a multidrug regimen for resistant high blood pressure that attacks the volume problem with a diuretic, that blocks the renin–angiotensin–aldosterone system with an ARB, and that further lowers blood pressure with a calcium-channel blocker,” said Dr. Oparil in an interview.

The objective of the phase 3, multicenter, parallel-group Triple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study (TRINITY) was to compare the coadministration of OM 40 mg/AML 10 mg/HCTZ 25 mg (n = 627) with corresponding dual components: OM/AML (n = 628), OM/HCTZ (n = 637), and AML/HCTZ (n = 600). The primary endpoint was the change from baseline to week 12 in diastolic BP for OM/AML/HCTZ in comparison to the corresponding dual treatments.

OM/AML/HCTZ resulted in significantly greater mean reductions in diastolic BP (21.8 vs. 15.1–18 mm Hg) and systolic BP (37.1 vs. 27.5–30 mm Hg), compared with corresponding therapy with two-drug combinations. The differences were reported after 12 weeks of therapy and at earlier measurements after 6, 8, and 10 weeks (P < 0.0001 for all comparisons). In addition, a significantly greater percentage of patients receiving OM/AML/HCTZ, compared with dual components, reached the BP target of below 140/90 mm Hg (69.9% vs. 41.1–53.4%; P < 0.0001 for all comparisons).

Subgroup analyses showed percentages of patients reaching BP target with triple versus dual therapy to be significantly greater regardless of sex, age, race, or severity of hypertension. In addition, 24-hour ambulatory BP monitoring revealed consistently greater effects for triple therapy.

All regimens were similarly well tolerated in the subgroups. The number of serious AEs was low for all regimens (1.2–1.7%), and few withdrawals were attributed to treatment-related AEs, as follows: 0.7% for OM 40 mg/AML 10 mg and 3.1% for OM 40 mg/AML 10 mg/HCTZ 25 mg. Peripheral edema was higher in the AML-containing regimens (7%–8.3% vs. 1% for OM 40/HCTZ 25 mg).

Dr. Oparil commented:

There’s a substantial population of patients in the U.S. who are older, who have some renal dysfunction, and perhaps diabetes who need three drugs. The advantage of this combination is that it will, if approved, be available in appropriate doses. I see a lot of patients with resistant hypertension who come in on five or six drugs—but they are the wrong combinations. The drugs don’t work together or the doses are too low. Instead of escalating the dose properly, primary care doctors sometimes just add more drugs. This will address that and be convenient and achieve pretty good control rates.

Some believe, she added, that OM has more powerful BP-lowering capacity than other approved ARBs.

Azilsartan For Primary Hypertension

  • George Bakris, MD, Professor of Medicine, University of Chicago Medical School, Chicago, Ill.
  • William B. White, MD, Professor of Medicine, University of Connecticut School of Medicine, Farmington, Conn.

Chlothalidone (Thalitone) plus HCTZ with Azilsartan

Chlorthalidone (CLTD [Thalitone, Monarch/King]), a longer-acting, thiazide-like diuretic than HCTZ, is by far less commonly prescribed, even though CTLD was used in the major U.S. cardiovascular clinical trials of hypertension, said Dr. Bakris.

A double-bind, randomized clinical trial comparing CLTD and HCTZ, both in combination with the investigational angiotensin-receptor blocker (ARB) azilsartan medoxomil (AZL-M, TAK-491, Takeda), demonstrated superior BP effects with AZL-M/CLTD. The investigators’ aim was to compare the efficacy, safety, and tolerability of AZL-M 40 mg in a fixed-dose combination of CLTD 12.5 mg (with doses titrated, if needed, to 25 mg with AZL-M 40 mg) plus AZL-M 40 mg in free combination with HCTZ (with the 12.5-mg dose titrated, if needed, to 25 mg).

Patients with a clinical BP of 160 to 190 mm Hg received AZL-M as monotherapy for one week, then AZL-M combined with one of the lower-dose diuretics for five weeks. If necessary, the diuretic dose was titrated upward at week 6, with treatment continuing for four additional weeks. The primary efficacy endpoint was a change in systolic BP from the baseline to weeks 6 and 10.

Baseline systolic and diastolic clinical BP values were about 165 mm Hg and 95 mm Hg, respectively. Ninety-three patients (30.8%) in the CLTD group (n = 303) required the higher 25-mg dose, compared with 139 patients (45.9%) in the HCTZ group (n = 306). Mean age among the 609 patients was approximately 56 years, and the mean BMI was approximately 31 kg/m2.

Systolic BP reductions were significantly greater with AZL-M/CLTD at 35.1 mm Hg, compared with AZL-M/HCTZ at 29.5 mm Hg (P < 0.001). At week 10, the changes were −37.8 mm Hg with AZL-M/CLTD and −32.8 mm Hg with AZL-M/HCTZ (P < 0.001).

At six weeks, 24-hour ambulatory BP monitoring revealed reductions of 25.7 mm Hg and 19.9 mm Hg (from approximately146 mm Hg) in the AZL-M/CLTD and AZL-M/HCTZ groups, respectively. At 10 weeks, BOP decreased by 26.6 mm Hg and by 22.4 mm Hg, respectively (P < 0.001).

Serious AEs were reported at similar rates for the two treatment groups—at 2% for AZL-M/CLTD and at 1.7% for AZL-M/HCTZ. One sudden death was considered possibly related to the study drug (AZL-M/HCTZ). Discontinuation of the study medication resulting from AEs occurred at rates of 9.3% for AZL-M/CLTD and at 7.3% for AZL-M/HCTZ.

For this patient population with stage 2 hypertension, Dr. Bakris concluded: “Azilsartan plus chlorthalidone in a fixed-dose combination provided greater antihypertensive efficacy than azilsartan plus hydrochlorothiazide.”

Comparison of Azilsartan with Olmesartan (Benicar) and Valsartan (Diovan)

Dr. White reported a further study of the investigational ARB azilsartan medoxomil (AZL-M). He compared AZL-M with two other approved ARBs, olmesartan (Benicar) and valsartan (Diovan, Novartis). At its maximal dose of 80 mg, AZL-M reduced ambulatory BP significantly more than the other two ARBs. He concluded that AZL-M had superior 24-hour BP-lowering efficacy compared with either olmesartan or valsartan.

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