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Combination therapy as the initial drug treatment for hypertension: when is it appropriate?
AJH
2001; 14:293–295
Combination Therapy as the Initial Drug Treatment for Hypertension: When Is It Appropriate? Barry J. Materson
O
scillations of the pharmacotherapeutic pendulum have been occurring for at least the past century. In the early 1900s, combination therapy was standard and it was common for complex prescriptions to be compounded on site by pharmacists. When single “silver bullet” medications became available for certain diseases, the philosophy shifted toward the use of singleentity therapy whenever possible. Modern data were generated supporting the use of single-drug therapy for the treatment of hypertension1,2 by the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. These data were most applicable to patients with stage 1 hypertension. On the other hand, the concept of combination therapy is far from dead. In the Far East today, herbalists by various titles compound complex mixtures. In the Western world, lay persons self-prescribe numerous vitamins and supplements. They may rely on the Internet or health food store sales clerks for advice on the use of these products, almost none of which meet the rigid criteria for prescription drugs. The general public is used to combination and multidrug (or multisubstance) therapy. Now we are accustomed to multidrug therapy for cancer, AIDS, tuberculosis, and even hypertension. Hypertension was one disorder that was treated early on with multiple drugs, mostly owing to the fact that no single drug was very efficacious or was too toxic to be used alone. The advent of thiazide diuretics in the late 1950s made combination therapy far more efficacious and much safer. The classic Veterans Administration studies3–5 chaired by Dr. Edward D. Freis, which proved that antihypertensive therapy reduced death and target organ damage, used a combination of reserpine, hydralazine, and hydrochlorothiazide. Contemporaneously, new effective and safe antihypertensive medications became available. The result was that it became possible to treat a substantial number of hypertensive patients with a single drug, especially if they
established a healthy lifestyle (nonpharmacologic therapy) as a basis for drug therapy. About two-thirds of patients with documented hypertension are at stage 1 (ie, systolic pressure 140 to 159 and diastolic pressure 90 to 99 mm Hg). These patients have the greatest chance of responding to single-drug therapy. There is no absolute agreement on what the initial single drug should be. The Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC) early on recommended a thiazide diuretic as initial therapy. JNC-III responded to new evidence by making a diuretic or -blocker coequals for initial therapy. The next iteration suggested one of four drugs: diuretic, -blocker, angiotensin converting enzyme inhibitor (ACEI), or calcium antagonist. Some physicians felt that ␣1-antagonists should have been included. JNC-V retracted this broad recommendation because evidence for target organ protection and decreased mortality was available only for diuretics and -blockers. The most recent recommendation (JNC-VI)6 stays with a diuretic or -blocker for patients with uncomplicated hypertension who have no other specific indication or contraindication. They then added combination therapy as a possible strategy. JNC-VI was fairly specific about its recommendations for initial low-dose combination therapy:
Received July 17, 2000. Accepted July 17, 2000. From the Department of Medicine, University of Miami School of Medicine, Miami, Florida.
Address correspondence to Dr. Barry J. Materson, University of Miami (M-854), 1150 NW 14th Street (Suite 105), Miami, FL 33136; e-mail: [email protected]
© 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
1.
2. 3.
4.
Very low-dose diuretic (eg, 6.25 mg of hydrochlorothiazide) to potentiate the effect of another agent (eg, bisoprolol) while minimizing the risk of adverse effects. ACEI and nondihydropyridine calcium antagonists to reduce proteinuria more than either drug alone. ACEI and dihydropyridine calcium antagonist, which may induce less pedal edema than the dihydropyridine alone. Single drugs that might have fewer adverse effects if used in lower dose with a diuretic (e.g., direct-acting smooth muscle vasodilators, central ␣2-agonists, peripheral adrenergic antagonists).
0895-7061/01/$20.00 PII S0895-7061(00)01259-0
294
INITIAL COMBINATION THERAPY FOR HYPERTENSION
During the past quarter century, evidence has accumulated to support the treatment of blood pressure at lower and lower levels of elevation.6 We would therefore suggest the following additional reasons to use combination therapy as initial therapy: 1. 2.
3.
4.
Stage 2 or higher hypertension, simply because it is less likely to respond to a single drug. Proteinuria such that systolic blood pressure must be reduced to ⬍ 125 mm Hg and baseline blood pressure is sufficiently high that one drug is not likely to achieve that goal. (An ACE inhibitor/thiazide combination would be a suggested start). Diabetes mellitus for which an ACE inhibitor is indicated but would not likely control blood pressure to ⱕ 130 mm Hg. Renal failure such that a single drug would be unlikely to control the blood pressure to ⱕ 130 mm Hg. (An ACE inhibitor or an angiotensin receptor blocker should be part of the combination).
The Department of Veterans Affairs Cooperative Study Group on antihypertensive Agents has substantial experience with antihypertensive drug combinations.7 Most of these studies provide data on combinations of a variety of drugs with a diuretic. In every such instance, the diuretic provided at least additive therapeutic efficacy. The VA trial of single-drug therapy had two additional substudies for patients who failed to achieve goal blood pressure with the initial, randomly assigned drug therapy. In the first of these, patients were exposed to a randomly selected alternate active single drug, but not to placebo. The data from that trial tended to validate the initial trial data and also supported a strategy of sequential drug therapy.8 That is, for a patient with stage 1 or 2 hypertension for whom there is ample time to discover an effective single drug, one might legitimately offer an alternative single drug, preferably based on age by race interaction subgroups. Many patients will respond to that alternative single drug. This generally does require the full understanding and cooperation of the patient. If a patient is overly anxious to see a complete therapeutic response, this strategy may not be wise. The second substudy9 pertained to those 102 patients who had failed to achieve goal blood pressure on each of two attempts at single-drug therapy. This provided an opportunity to test the therapeutic efficacy of the two single drugs in combination. Indeed, the results of the combination were impressive: ⬎ 80% of the patients achieved goal blood pressure with each combination. In many combinations, the results were ⬎ 90%. Keep in mind that this was not a previously untreated population, but one that had failed each of two attempts at single-drug therapy. In general, combinations of any drug with hydrochlorothiazide gave better results than did the combinations of two nondiuretic drugs. The nondiuretic drugs that were combined were atenolol, captopril, clonidine, diltiazem-SR, and prazosin.
AJH–March 2001–VOL. 14, NO. 3
Despite the contrived point– counterpoint approach to this issue, I remain a firm believer in the autonomy of intelligent physicians. I expect them to be able to follow data-based algorithms and guidelines, but I also expect them to recognize when a given patient falls outside of those algorithms or guidelines and then to act according to the best data available in addition to their own clinical experience. The above philosophy and the information that I have presented above prevent me from taking a rigid, contrived, one-sided position. Having expressed that line of thought, it is my opinion that hypertensive patients should be treated with a single drug whenever it is possible to do so. At least half of all hypertensive patients should be amenable to such therapy, and I believe that it is unwise to expose them unnecessarily to more than one drug. If the single drug or its sequential substitute fails to achieve goal blood pressure, then addition of a second drug (particularly a diuretic if not first selected) is one appropriate strategy. An alternate appropriate strategy would be to prescribe a combination drug. Any hypertensive patient who meets the criteria elaborated by JNC-VI or my additional criteria as noted above would be a good candidate for initial combination therapy. Again, there is no substitute for good communication with the patient so that he or she fully understands your strategy and goals. This can be accomplished effectively by means of prepared brochures or videotapes, or with the help of allied health personnel. It should surprise no one that I believe this approach to be rational, reasonable, databased, practical, and potentially economical.
References 1.
2.
3.
4.
5.
6.
Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, Hamburger RJ, Fye C, Lakshman R, Gottdiener J, Ramirez EA, Henderson WG: Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. N Engl J Med 1993;328:914 –921. Materson BJ, Reda DJ, Cushman WC, for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents: Department of Veterans Affairs Single-Drug therapy of hypertension study: revised figures and new data. Am J Hypertens 1995;8: 189 –192. Veterans Administration Cooperative Study Group on Anti-hypertensive Agents: Effects of treatment on morbidity in hypertension. I. Results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA 1967;202:1028 –1034. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. I. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970;213:1143–1152. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. III. Influence of age, diastolic pressure, and prior cardiovascular disease: further analysis of side effects. Circulation 1972;45:991–1004. Joint National Committee on Prevention, Detection, Evaluation, 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.
AJH–March 2001–VOL. 14, NO. 3
7. 8.
INITIAL COMBINATION THERAPY FOR HYPERTENSION
Materson BJ, Reda DJ, Williams D: Lessons from combination therapy in Veterans Affairs studies. Am J Hypertens 1996;9:187S–191S. Materson BJ, Reda DJ, Preston RA, Cushman WC, Massie BM, Freis ED, Kochar MS, Hamburger RJ, Fye C, Lakshman R, Gottdiener J, Ramirez EA, Henderson WG, for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents: Response to a second single antihypertensive agent used as
9.
295
monotherapy for hypertension after failure of the initial drug. Arch Intern Med 1995;155:1757–1762. Materson BJ, Reda DJ, Cushman WC, Henderson WG, for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents: Results of combination anti-hypertensive therapy after failure of each of the components. J Hum Hypertens 1995;9:791–796.
2001; 14:293–295
Combination Therapy as the Initial Drug Treatment for Hypertension: When Is It Appropriate? Barry J. Materson
O
scillations of the pharmacotherapeutic pendulum have been occurring for at least the past century. In the early 1900s, combination therapy was standard and it was common for complex prescriptions to be compounded on site by pharmacists. When single “silver bullet” medications became available for certain diseases, the philosophy shifted toward the use of singleentity therapy whenever possible. Modern data were generated supporting the use of single-drug therapy for the treatment of hypertension1,2 by the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. These data were most applicable to patients with stage 1 hypertension. On the other hand, the concept of combination therapy is far from dead. In the Far East today, herbalists by various titles compound complex mixtures. In the Western world, lay persons self-prescribe numerous vitamins and supplements. They may rely on the Internet or health food store sales clerks for advice on the use of these products, almost none of which meet the rigid criteria for prescription drugs. The general public is used to combination and multidrug (or multisubstance) therapy. Now we are accustomed to multidrug therapy for cancer, AIDS, tuberculosis, and even hypertension. Hypertension was one disorder that was treated early on with multiple drugs, mostly owing to the fact that no single drug was very efficacious or was too toxic to be used alone. The advent of thiazide diuretics in the late 1950s made combination therapy far more efficacious and much safer. The classic Veterans Administration studies3–5 chaired by Dr. Edward D. Freis, which proved that antihypertensive therapy reduced death and target organ damage, used a combination of reserpine, hydralazine, and hydrochlorothiazide. Contemporaneously, new effective and safe antihypertensive medications became available. The result was that it became possible to treat a substantial number of hypertensive patients with a single drug, especially if they
established a healthy lifestyle (nonpharmacologic therapy) as a basis for drug therapy. About two-thirds of patients with documented hypertension are at stage 1 (ie, systolic pressure 140 to 159 and diastolic pressure 90 to 99 mm Hg). These patients have the greatest chance of responding to single-drug therapy. There is no absolute agreement on what the initial single drug should be. The Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC) early on recommended a thiazide diuretic as initial therapy. JNC-III responded to new evidence by making a diuretic or -blocker coequals for initial therapy. The next iteration suggested one of four drugs: diuretic, -blocker, angiotensin converting enzyme inhibitor (ACEI), or calcium antagonist. Some physicians felt that ␣1-antagonists should have been included. JNC-V retracted this broad recommendation because evidence for target organ protection and decreased mortality was available only for diuretics and -blockers. The most recent recommendation (JNC-VI)6 stays with a diuretic or -blocker for patients with uncomplicated hypertension who have no other specific indication or contraindication. They then added combination therapy as a possible strategy. JNC-VI was fairly specific about its recommendations for initial low-dose combination therapy:
Received July 17, 2000. Accepted July 17, 2000. From the Department of Medicine, University of Miami School of Medicine, Miami, Florida.
Address correspondence to Dr. Barry J. Materson, University of Miami (M-854), 1150 NW 14th Street (Suite 105), Miami, FL 33136; e-mail: [email protected]
© 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
1.
2. 3.
4.
Very low-dose diuretic (eg, 6.25 mg of hydrochlorothiazide) to potentiate the effect of another agent (eg, bisoprolol) while minimizing the risk of adverse effects. ACEI and nondihydropyridine calcium antagonists to reduce proteinuria more than either drug alone. ACEI and dihydropyridine calcium antagonist, which may induce less pedal edema than the dihydropyridine alone. Single drugs that might have fewer adverse effects if used in lower dose with a diuretic (e.g., direct-acting smooth muscle vasodilators, central ␣2-agonists, peripheral adrenergic antagonists).
0895-7061/01/$20.00 PII S0895-7061(00)01259-0
294
INITIAL COMBINATION THERAPY FOR HYPERTENSION
During the past quarter century, evidence has accumulated to support the treatment of blood pressure at lower and lower levels of elevation.6 We would therefore suggest the following additional reasons to use combination therapy as initial therapy: 1. 2.
3.
4.
Stage 2 or higher hypertension, simply because it is less likely to respond to a single drug. Proteinuria such that systolic blood pressure must be reduced to ⬍ 125 mm Hg and baseline blood pressure is sufficiently high that one drug is not likely to achieve that goal. (An ACE inhibitor/thiazide combination would be a suggested start). Diabetes mellitus for which an ACE inhibitor is indicated but would not likely control blood pressure to ⱕ 130 mm Hg. Renal failure such that a single drug would be unlikely to control the blood pressure to ⱕ 130 mm Hg. (An ACE inhibitor or an angiotensin receptor blocker should be part of the combination).
The Department of Veterans Affairs Cooperative Study Group on antihypertensive Agents has substantial experience with antihypertensive drug combinations.7 Most of these studies provide data on combinations of a variety of drugs with a diuretic. In every such instance, the diuretic provided at least additive therapeutic efficacy. The VA trial of single-drug therapy had two additional substudies for patients who failed to achieve goal blood pressure with the initial, randomly assigned drug therapy. In the first of these, patients were exposed to a randomly selected alternate active single drug, but not to placebo. The data from that trial tended to validate the initial trial data and also supported a strategy of sequential drug therapy.8 That is, for a patient with stage 1 or 2 hypertension for whom there is ample time to discover an effective single drug, one might legitimately offer an alternative single drug, preferably based on age by race interaction subgroups. Many patients will respond to that alternative single drug. This generally does require the full understanding and cooperation of the patient. If a patient is overly anxious to see a complete therapeutic response, this strategy may not be wise. The second substudy9 pertained to those 102 patients who had failed to achieve goal blood pressure on each of two attempts at single-drug therapy. This provided an opportunity to test the therapeutic efficacy of the two single drugs in combination. Indeed, the results of the combination were impressive: ⬎ 80% of the patients achieved goal blood pressure with each combination. In many combinations, the results were ⬎ 90%. Keep in mind that this was not a previously untreated population, but one that had failed each of two attempts at single-drug therapy. In general, combinations of any drug with hydrochlorothiazide gave better results than did the combinations of two nondiuretic drugs. The nondiuretic drugs that were combined were atenolol, captopril, clonidine, diltiazem-SR, and prazosin.
AJH–March 2001–VOL. 14, NO. 3
Despite the contrived point– counterpoint approach to this issue, I remain a firm believer in the autonomy of intelligent physicians. I expect them to be able to follow data-based algorithms and guidelines, but I also expect them to recognize when a given patient falls outside of those algorithms or guidelines and then to act according to the best data available in addition to their own clinical experience. The above philosophy and the information that I have presented above prevent me from taking a rigid, contrived, one-sided position. Having expressed that line of thought, it is my opinion that hypertensive patients should be treated with a single drug whenever it is possible to do so. At least half of all hypertensive patients should be amenable to such therapy, and I believe that it is unwise to expose them unnecessarily to more than one drug. If the single drug or its sequential substitute fails to achieve goal blood pressure, then addition of a second drug (particularly a diuretic if not first selected) is one appropriate strategy. An alternate appropriate strategy would be to prescribe a combination drug. Any hypertensive patient who meets the criteria elaborated by JNC-VI or my additional criteria as noted above would be a good candidate for initial combination therapy. Again, there is no substitute for good communication with the patient so that he or she fully understands your strategy and goals. This can be accomplished effectively by means of prepared brochures or videotapes, or with the help of allied health personnel. It should surprise no one that I believe this approach to be rational, reasonable, databased, practical, and potentially economical.
References 1.
2.
3.
4.
5.
6.
Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, Hamburger RJ, Fye C, Lakshman R, Gottdiener J, Ramirez EA, Henderson WG: Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. N Engl J Med 1993;328:914 –921. Materson BJ, Reda DJ, Cushman WC, for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents: Department of Veterans Affairs Single-Drug therapy of hypertension study: revised figures and new data. Am J Hypertens 1995;8: 189 –192. Veterans Administration Cooperative Study Group on Anti-hypertensive Agents: Effects of treatment on morbidity in hypertension. I. Results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA 1967;202:1028 –1034. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. I. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970;213:1143–1152. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. III. Influence of age, diastolic pressure, and prior cardiovascular disease: further analysis of side effects. Circulation 1972;45:991–1004. Joint National Committee on Prevention, Detection, Evaluation, 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.
AJH–March 2001–VOL. 14, NO. 3
7. 8.
INITIAL COMBINATION THERAPY FOR HYPERTENSION
Materson BJ, Reda DJ, Williams D: Lessons from combination therapy in Veterans Affairs studies. Am J Hypertens 1996;9:187S–191S. Materson BJ, Reda DJ, Preston RA, Cushman WC, Massie BM, Freis ED, Kochar MS, Hamburger RJ, Fye C, Lakshman R, Gottdiener J, Ramirez EA, Henderson WG, for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents: Response to a second single antihypertensive agent used as
9.
295
monotherapy for hypertension after failure of the initial drug. Arch Intern Med 1995;155:1757–1762. Materson BJ, Reda DJ, Cushman WC, Henderson WG, for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents: Results of combination anti-hypertensive therapy after failure of each of the components. J Hum Hypertens 1995;9:791–796.