ACCOMPLISH: Fixed-Dose Combination at Outset Improves BP Control

Internal Medicine World Report, July 2007, Volume 0, Issue 0

Initiate Aggressive Antihypertensive Therapy Early

By Wayne Kuznar

Kenneth

Jamerson, MD

CHICAGO?Using a fixed-dose, 2-drug combination tablet as initial therapy gets three fourths of high-risk hypertensive patients to their blood pressure (BP) goal by 18 months, show preliminary data from an ongoing study comparing 2 fixed-dose combinations.

The study, Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH), is comparing outcomes among patients with hypertension treated with benazepril/amlodipine (Lotrel) or benazepril/hydrochlorothiazide. Blinded BP control data at 18 months were released at the American Society of Hypertension annual meeting. ?When physicians prescribe medications, we had this old mantra, 'Start low, go slow.' We decided that what makes more sense is to initiate aggressive therapy, and initiate it quickly, and we might get better outcomes," said Kenneth Jamerson, MD, lead investigator of ACCOMPLISH. "A new paradigm shift is to use combination therapy at the initiation of treatment to try to get better outcomes."

Although fixed-dose combination therapy has been advocated by some experts for sometime now, according to national treatment guidelines, such therapy has generally been reserved for patients with BP ≥160/100 mm Hg at the outset (stage 2 hypertension), pointed out Dr Jamerson, professor of internal medicine, University of Michigan, Ann Arbor. A thiazide diuretic as part of this 2-drug combination is also recommended by current guidelines.

"We think that there may be some combinations out there that may be a little better, particularly the combination of an ACE [angiotensin-converting-enzyme] inhibitor and calcium channel blocker," Dr Jamerson said. "There's a lot of experimental evidence to suggest that both of these converge to increase the amount of nitric oxide that's available, thereby improving overall vascular health."

Nearly all (97%) of the 11,400 patients enrolled in ACCOMPLISH were treated previously for hypertension, and 74% were treated with ≥2 antihypertensive agents. Despite such treatment, their systolic BP (SBP) on entering the trial was 145.4 mm Hg.

Dosages in ACCOMPLISH were titrated to achieve a target BP <140/90 mm Hg (<130/80 mm Hg in patients with diabetes or renal insufficiency).

By 6 months, mean SBP fell to 132.5 mm Hg, and by 18 months it dropped further to 131.8 mm Hg. Neither age nor gender influenced the effects on SBP.

In the 6921 patients with diabetes, SBP decreased from 145.2 mm Hg at baseline to 131.5 mm Hg at 18 months. In the 680 patients with chronic kidney disease, it fell from 148.7 mm Hg at baseline to 136.2 mm Hg at 18-month follow-up.

Control rates in the overall study population increased from 37.6% at baseline to 75.6% at 18 months. Up to 80.5% of the 8067 US trial participants achieved BP control.

Although add-on therapy was allowed in the trial, about two thirds of the patients had their BP controlled with the study drug only, noted Dr Jamerson. About one third of patients required add-on therapy in an attempt to achieve their BP goal.

Outcomes data from ACCOMPLISH are expected in 2008.

KEY POINTS

  • Using a fixed-dose, 2-drug combination pill at the outset resulted in three fourths of high-risk hypertensives reaching BP goals by 18 months in ACCOMPLISH.
  • Although add-on therapy was permitted, most patients? BP was controlled with the study drug only.
  • Experts suggest a paradigm shift, advising early initiation of fixed-dose combination therapy to improve outcomes.
  • Drawbacks include a lack of dosage flexibility and difficulty attributing side effects to a particular drug.

According to William Elliott, MD, PhD, professor of preventive medicine, internal medicine and pharmacology, Rush Medical College, Chicago, early initiation of combination antihypertensive therapy for patients with stage 2 hypertension may help them reach BP goals earlier. He noted that the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial showed that achieving BP goals early was associated with a 25% reduction in cardiovascular events compared with achieving BP goals later. In addition, the reduction in the incidence of stroke and death occurred as early as 1 month in the group with better early BP control.

Drawbacks to initiating therapy with a fixed-dose combination include a lack of dosage flexibility and difficulty in attributing side effects to a particular drug when the drugs included in the combination have similar side-effect profiles, said Dr Elliott.