Friday, November 4, 2011

Articles that changed the way I practice: ACCOMPLISH

I was searching PBFluids and could not find any posts about ACCOMPLISH which surprised me. I then went to the Renal Fellow Network and found a similar lack of commentary. Dito for Nephron Power, and Nephrology on Demand. Even The Kidney Doctor with 100+ posts (and in the process putting the rest of the nephrology blogosphere to shame) in the last 2 months comes up empty handed.

Now some of this may be due to faulty blog search and some of this may be due to the fact that the study is approaching 3 years of age, but regardless ACCOMPLISH is important enough that it should get higher profile coverage.

The study was published in the NEJM in 2008

The acronym is an obviously:
  • Avoiding 
  • Cardiovascular events through 
  • COmbination therapy in 
  • Patient 
  • LIving with 
  • Systolic 
  • Hypertension
From the title, if not the acronym, the point of the study should be clear: The study pits benazepril and amlodipine (Lotrel) against benazepril and hydrochlorothiazide (Lotensin).

The politics of this fight are interesting as this study tries to right one of the possible mis-steps in the wake of ALLHAT. ACCOMPLISH used the thiazide diuretic that is actually most often used in the U.S. and the only thiazide that is used in combination pills, hydrochlorothiazide (yes I know I'm ignoring Tenoretic, atenolol and chlorthalidone, but every other combination pill uses hydrochlorothiazide). ALLHAT used chlorthalidone as its diuretic and when this largest-ever hypertension study concluded that there was no difference among chlorthalidone, amlodipine and lisinopril on fatal coronary heart disease and non-fatal heart attacks, thiazides became institutionalized as the primary agent to treat hypertension.

Figure depicting the primary outcome from ALLHAT
The money shot from JNC7 (pdf) institutionalizing thiazide-type diuretics
The problem stems from the fact that hydrochlorothiazide and chlorthalidone are unique molecules with significant biologic and pharmacokinetic differences.

This year Dorsch et al re-analyzed data from the MRFIT trial. This was a long-term primary prevention trial from the 70's that changed protocols mid-stream and converted patients from HCTZ to chlorthalidone. This allowed Dorsch's team to look for differential effects of the two diuretics. They found a 21% reduction in cardiovascular events with chlorthalidone:

If you are interested in the reasons behind the differences read John Flack's editorial associated with Dorsch's analysis and look at a 2004 review by Carter et al.

So ACCOMPLISH set out to show that the ACEi CCB combination is superior to the ACEi HCT combination. They randomized 11,506 patients to one of these two arms. The dosing titration seems fair:
  1. 20 benazepril and either 5 of amlodipine or 12.5 of dydrochlorothiazide
  2. if BP is not < 140/90 (130/80 in CKD and DM) increase to 40 mg of benazepril
  3. if BP is not < 140/90 (130/80 in CKD and DM)  increase to 10 of amlodipine or 25 of hydrochlorothiazide
  4. if BP is not < 140/90 (130/80 in CKD and DM)  add additional agents as needed
The cohort was rather sick with previously diagnosed hypertension and an additional history of at least one of the following:
  • Coronary events
  • Impaired renal function
  • Peripheral artery disease
  • LVH
  • Diabetes.
The end point was time to first cardiovascular event, or death from cardiovascular disease.

The study was well run but the blood pressures were not perfectly equal between groups with a small but statistically signifigant difference in the blood pressures between the two groups:
  • 131.6/73.3 in the Benazepril-Amlodipine group
  • 132.5/74.4 in the Benazepril-Hydrochlorothiazide group
  • A difference of 0.9/1.1 in favor of the Benazepril-Amlodipine group

The study was terminated early because the data and safety monitoring committee observed a difference between the two groups that exceeded the pre-specified stopping rule. They found a 20% risk reduction in only 30 months. This represented an absolute risk reduction of 2.2% which translates into a Number Needed to Treat of only 45.

Entering EBM free zone:

To my eyes, ACCOMPLISH better represents the patients I see than ALLHAT. All of the patients that come to my CKD clinic have high blood pressure and almost all also have the additional co-morbidities needed for enrollment. After fully digesting ACCOMPLISH I have made two changes in my practice pattern:

  1. I am starting patients with ACEi + CCB or ARB + CCB. I have been impressed by the effectiveness of Lotrel and Exforge as single pill solutions to a lot of hypertension.
  2. I avoiding hydrochlorothiazide where ever possible. This usually requires re-jiggering a number of medications but a common switch will be to move patients from a list that looks like this:
    1. Lisinopril HCT
    2. Amlodipine
          To a list that looks like this:

    1. ACEi CCB combination pill
    2. Chlorthalidone
This results in significant improvement in blood pressure control.
I have to thank ACCOMPLISH to opening my eyes to this change.
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