According to the JNC 7 guidelines, use of fixed low-dose combination
therapy with any of several different approved combinations of antihypertensive
agents can be recommended. However, for which of the following reasons
is fixed-dose therapy not generally applicable?To improve patient adherence
to therapy
As a "standard of care" for all patients with blood pressure
levels > 140/90 mm Hg
To minimize side effects by using lowest effective doses of each agent
To provide a rapid response in those patients requiring a 20/10-mm Hg
decrement in blood pressure levels
1. To improve patient
adherence to therapy
2. As a "standard of care" for all patients
with blood pressure levels > 140/90 mm Hg
3. To minimize side effects by using lowest effective doses of each
agent
4. To provide a rapid response in those patients requiring a 20/10-mm
Hg decrement in blood pressure levels
Fixed-dose Therapy
One of the important recommendations of
the JNC 7 guidelines applies to those patients who are initially diagnosed
with blood pressure levels more than 20/10 mm Hg above goal. For these
patients, or those whose levels increase to these elevations, the guidelines
recommend that consideration should be given to initiating therapy with
2 drugs, either as separate prescriptions "or in fixed-dose combinations."
Thus, one of the important tenets of the
new JNC 7 guidelines is that fixed low-dose combinations -- because
of their simplicity of use and the fact that they improve the blood
pressure response rate while minimizing the incidence of adverse effects
-- should be considered as suitable for not only second-line, but even
as first-line therapy in those patients requiring a 20/10-mm Hg decrement
in blood pressure levels.
Although at present there are no large,
well-controlled clinical trial results to distinguish among the various
combinations, several fixed-dose combination therapies are currently
available for treating hypertension (see Table 2).
ACE, angiotensin-converting enzyme;
ARB, angiotensin receptor blocker; CCB, calcium channel blocker;
HCTZ, hydrochlorothiazide
SOURCE: US Department of Health and Human Services. JNC 7 Express.
The Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure.
While the recommendation of the JNC 7 is
to use a combination that contains a diuretic, and many of the fixed-dose
combinations do add either an ACE inhibitor or an ARB to a diuretic,
one of the combinations that has been widely marketed, based on formulations
created before the current evidence-based guideline announcements, is
the combination of a calcium antagonist with an ACE inhibitor. This
combination is conceptually attractive[17] because the calcium
antagonist provides primarily arterial vasodilation, whereas the ACE
inhibitor adds some venous dilation, a characteristic that applies particularly
to the dihydropyridine calcium antagonists, and which produces an almost
exclusive arteriolar dilation. Each agent provides theoretical or actual
benefits when certain other conditions are present: ACE inhibitors have
been shown to have efficacy against left ventricular dysfunction/heart
failure, diabetic nephropathy, and postmyocardial infarction, whereas
the calcium antagonists provide protection against angina, certain arrhythmias,
and various vasospastic conditions. In addition, in theory both agents
have beneficial effects on the kidney, heart, and vasculature that are
pressure-independent.
Further evidence in favor of this combination
strategy, albeit without the fixed-dose feature, comes from the recently
presented clinical trial, INternational VErapamil SR/trandolapril STudy
(INVEST).[18] In this trial, the ACE inhibitor trandolapril
was used as an add-on agent with a nondihydropyridine calcium channel
blocker (verapamil) in more than 22,000 hypertensive patients. Per trial
design, the results demonstrated equivalence for this combination in
reducing CVD mortality in hypertensive patients with coronary disease
when compared with a beta-blocker/diuretic combination.
A further example of this combination strategy,
in this case as a fixed-dose combination of amlodipine plus benazepril
(marketed as Lotrel), has been under active investigation in
several clinical trials. The first trial, Lotrel: Gauging Improved
Control (LOGIC), demonstrated that this combination alleviated pedal
edema (swelling of the feet and legs), a common side effect of amlodipine
monotherapy.[19]
The results of a second trial with this
combination, Study of Hypertension and the Efficacy of Lotrel
in Hypertensive Diabetics (SHIELD),[20] demonstrated that
Patients with type 2 diabetes taking the combination reached goal
blood pressure (</= 130/85 mm Hg) faster than those patients who
started with enalapril monotherapy and later had a diuretic added.
The combination provided significantly greater decrements in mean
sitting SBP and DBP than monotherapy with enalapril (SBP: -20.5 vs
-14.5 mm Hg, P = .002; DBP -13.9 vs -9.6 mm Hg, P =
.001, respectively).
Neither treatment showed any adverse effects on glycemic control.
Both treatment approaches were well tolerated.
Finally, at the 2003 American Heart Association
conference, it was announced that a new trial involving nearly 13,000
patients, Avoiding Cardiovascular Events through COMbination Therapy
in Patients LIving with Systolic Hypertension (ACCOMPLISH), would be
initiated. The trial will be the first morbidity/mortality trial to
initiate therapy with a fixed-dose antihypertensive treatment strategy.
Thus, until the anticipated completion date in 2005, a strategy of initiating
treatment with a fixed-dose combination of an ACE inhibitor and a calcium
antagonist must proceed on the basis of the theoretical considerations
outlined above.
References
Major Outcomes in High-Risk Hypertensive Patients Randomized to
Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker
vs Diuretic: The Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT). The ALLHAT Officers and Coordinators
for the ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-3007.
Joint National Committee on Prevention, Detection, and Treatment
of High Blood Pressure. The Sixth Report of the Joint National Committee
on prevention, detection, evaluation, and treatment of high blood
pressure. Arch Intern Med. 1997;157:2413-2446.
Dahlof B, Devereux RB, Kjeldsen S, et al. Cardiovascular morbidity
and mortality in the Losartan Intervention For Endpoint reduction
in hypertension study (LIFE): a randomized trial against atenolol.
Lancet. 2002;359:995-1003.
Wing LMH, Reid CM, Ryan P, et al, for the Second Australian National
Blood Pressure Study Group. A comparison of outcome with angiotensin-converting-enzyme
inhibitors and diuretics for hypertension in the elderly. N Engl J
Med. 2003;348:583-592.
US Department of Health and Human Services. JNC 7 Express. The Seventh
Report of the Joint National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure. Available on the NHLBI Web site
at http://www.nhlbi.nih.gov
or from the NHLBI Health Information Center, PO Box 30105, Bethesda,
MD 20824-0105. Phone 301-592-8573 or 240-629-3255 (TTY); Fax: 301-592-8563.
Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of
the Joint National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.
Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D. Assessment of frequency
of progression to hypertension in non-hypertensive participants in
the Framingham Heart Study: a cohort study. Lancet. 2001;358:1682-1686.
United States Department of Health and Human Services Centers for
Disease Control and Prevention. National Health and Nutrition Examination
Survey IV (NHANES IV). 1999-2000 Data Files http://www.cdc.gov/nchs/about/major/nhanes/NHANES99_00.htm
United States Department of Health and Human Services Centers for
Disease Control and Prevention. National Health and Nutrition Examination
Survey III (NHANES III) http://www.cdc.gov/nchs/
about/major/nhanes/nh3data.htm. Accessed June 20, 2003.
U.S. Department of Health and Human Services. Healthy People
2010: Understanding and Improving Health. 2nd ed. Washington,
DC: U.S. Government Printing Office, November 2000.
Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective
Studies Collaboration. Age-specific relevance of usual blood pressure
to vascular mortality: a meta-analysis of individual data for one
million adults in 61 prospective studies. Lancet. 2002;360:1903-1913.
U.S. Department of Health and Human Services. National Institutes
for Health. Dietary Approaches to Stop Hypertension (DASH). Originally
Printed 1998, Reprinted February 1999, Revised May 2003. http://www.nhlbi.nih.gov/health/
public/heart/hbp/dash/new_dash.pdf. Accessed June 20, 2003.
Racial differences in response to low-dose captopril are abolished
by the addition of hydrochlorothiazide. Br J Clin Pharmacol. 1982;14:97S-101S.
Holland OB, von Kuhnert L, Campbell WB, Anderson RJ. Synergistic
effect of captopril with hydrochlorothiazide for the treatment of
low-renin hypertensive black patients. Hypertension. 1983;5:235-239.
Nicholson JP, Resnick LM, Laragh JH. Hydrochlorothiazide is not
additive to verapamil in treating essential hypertension. Arch Intern
Med. 1989;149:125-128.
Messerli FH. Combinations in the treatment of hypertension: ACE
Inhibitors and calcium antagonists. Am J Hypertens. 1999;12:86S-90S.
Pepine CJ, Handberg-Thurmond E, Marks RG, Conlon M, Cooper-DeHoff
R, Volkers P, Zellig P. Rationale and design of the International
Verapamil SR/Trandolapril Study (INVEST): an Internet-based randomized
trial in coronary artery disease patients with hypertension. J Am
Coll Cardiol. 1998;32:1228-1237.
