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?

  1. To improve patient adherence to therapy
    2.
  2. As a "standard of care" for all patients with blood pressure levels > 140/90 mm Hg
    3.
  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).

Table 2: Fixed-dose Combination Therapies

Combination Type

Fixed-dose Combination (mg)

Trade Name

ACE inhibitors and CCBs

Amlodipine/benazepril HCl (2.5/10, 5/10, 5/20, 20/25)
Enalapril maleate/felodipine (5/5)
Trandolapril/verapamil (2/180, 1/240, 2/240, 4/240)

Lotrel
Lexxel
Tarka

ACE inhibitors and diuretics

Benazepril/HCTZ (5/6.25, 10/12.5, 20/12.5, 20/25)
Captopril/HCTZ (25/15, 25/25, 50/15, 50/25)
Enalapril maleate/HCTZ (5/12.5, 10/25)
Lisinopril/HCTZ (10/12.5, 20/12.5, 20/25)
Moexipril HCl/HCTZ (7.5/12.5, 15/25)
Quinapril HCl/HCTZ (10/12.5, 20/12.5, 20/25)

Lotensin HCT
Capozide
Vaseretic
Prinzide
Uniretic
Accuretic

ARBs and diuretics

Candesartan cilexetil/HCTZ (16/12.5, 32/12.5)
Eprosartan mesylate/HCTZ (600/12.5, 600/25)
Irbesartan/HCTZ (150/12.5, 300/12.5)
Losartan potassium/HCTZ (50/12.5, 100/25)
Telmisartan/HCTZ (40/12.5, 80/12.5)
Valsartan/HCTZ (80/12.5, 160/12.5)

Atacand/HCT
Teveten/HCT
Avalide
Hyzaar
Micardis/HCT
Diovan/HCT

Beta blockers and diuretics

Atenolol/chlorthalidone (50/25, 100/25)
Bisoprolol fumarate/HCTZ (2.5/6.25, 5/6.25, 10/6.25)
Propranolol LA/HCTZ (40/25, 80/25)
Metoprolol tartrate/HCTZ (50/25, 100/25)
Nadolol/bendroflumethiazide (40/5, 80/5)
Timolol maleate/HCTZ (10/25)

Tenoretic
Ziac
Inderide
Lopressor HCT
Corzide
Timolide

Centrally acting drug and diuretic

Methyldopa/HCTZ (250/15, 250/25, 500/30, 500/50)
Reserpine/chlorothiazide (0.125/250, 0.25/500)
Reserpine/HCTZ (0.125/25, 0.125/50)

Aldoril
Diupres
Hydropres

Diuretic and diuretic

Amiloride HCl/HCTZ (5/50)
Spironolactone/HCTZ (25/25, 50/50)
Triamterene/HCTZ (37.5/25, 50/25, 75/50)

Moduretic
Aldactone
Dyazide, Maxzide

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

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

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. Racial differences in response to low-dose captopril are abolished by the addition of hydrochlorothiazide. Br J Clin Pharmacol. 1982;14:97S-101S.
  14. 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.
  15. Nicholson JP, Resnick LM, Laragh JH. Hydrochlorothiazide is not additive to verapamil in treating essential hypertension. Arch Intern Med. 1989;149:125-128.
  16. LifeClinic. Compliance Aids Available at:
    http://www.lifeclinic.com/ focus/blood/supply_aids.asp. Accessed June 20, 2003.
  17. Messerli FH. Combinations in the treatment of hypertension: ACE Inhibitors and calcium antagonists. Am J Hypertens. 1999;12:86S-90S.
  18. 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.