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Abstract

  1. Top of page
  2. Abstract
  3. POSSIBLE ADVANTAGES OF COMBINATION THERAPY
  4. WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?
  5. WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?
  6. THE PROGRESS TRIAL
  7. THE ALLHAT TRIAL
  8. THE ANBP-2 TRIAL
  9. DIFFERENCES BETWEEN ALLHAT AND ANBP-2
  10. THE CONVINCE TRIAL
  11. RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY
  12. DRUG INTERACTIONS
  13. NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY
  14. TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?
  15. QUESTIONS AND ANSWERS
  16. References

Combination drug therapy in the management of hypertension has been used for many years. Recent recommendations of the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and the results of several new multiple-drug trials have focused on using the approach as initial therapy in many hypertensive patients. Results of these long-term outcome trials, as well as short-term and smaller studies, indicate the advantage of multiple-drug therapy in the management of hypertension.

Combination therapies for the management of hypertension have been available for many years. Some data from the recent clinical trials provide a rationale for their continued and increasing use in the management of hypertension.

In the 1950s combination therapy was in common use.1 The medications that were combined were not ideal. Rauwolfia was an effective blood pressure (BP)-lowering drug but caused depression and sleepiness. Pentolinium (Ansolysen) was a ganglion blocker; fainting and sexual dysfunction were quite common with this agent. Hydralazine was a vasodilator that caused tachycardia and headaches. These were all used at one time or another in combination with a diuretic; BP lowering was impressive (Table I). At an American Heart Association Meeting, Henry Schroeder of St. Louis, MO, announced that he had found the cure for hypertension—a triple drug combination with the above medications.

Table I.  Early 1950s Preferred Therapy for Hypertension
A combination of rauwolfia and Ansolysen
A combination of hydralazine and hexamethonium
A combination of hydralazine, rauwolfia, and Ansolysen

In 1970 the most popular drug for hypertension in the United States was Ser-Ap-Es, a combination of Serpasil (a rauwolfia drug), Apresoline (hydralazine), and Esidrix (a thiazide diuretic). Thirty eight thousand doctors used it with sales of $16 million a year (Table II); compare that with sales of more than one billion dollars for several of our present drugs.

Table II.  Ser-Ap-Es (Reserpine 0.1 mg, Hydralazine 25.0 mg, and Hydrochlorothiazide 15.0 mg)
Leading drug for treatment of hypertension in 1970
Used by 38,000 doctors
Sales=$16 million/yr

Many other combinations have been used through the years. In the 1960s and 1970s there were combinations of thiazides and potassium-sparing agents and β blockers and thiazides. In the 1980s and 1990s, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) were combined with diuretics, and ACE inhibitors and calcium channel blockers (CCBs) became available as combinations2 (Table III).

Table III.  Examples of Fixed-Dose Combination Antihypertensive Agents
1960s
  Reserpine-hydralazine-hydrochlorothiazide
  Methyldopa/thiazide diuretic
1970s
  Thiazide/potassium-sparing diuretic
  Beta blocker/thiazide diuretic
1980s
  Angiotensin-converting enzyme inhibitor/thiazide diuretic
1990s
  Low-dose β blocker/thiazide diuretic
  Angiotensin-converting enzyme inhibitor/calcium channel blocker
  Angiotensin II receptor blocker/thiazide diuretic

In the Hypertension Detection and Follow-Up Program (HDFP)3 in the 1970s, triple drug therapy was used initially. Thus, the concept of combination therapy is an old one. In 1997 the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) suggested that low-dose combination therapy may be appropriate as initial treatment.4 This was criticized as being antiacademic. In 2003 the JNC 7 again suggested that combination therapy could be used as initial therapy and went a step further in advising that two medications were indicated as first-step therapy in patients with stage 2 hypertension (BPs geqslant R: gt-or-equal, slanted160/100 mm Hg) or in patients with stage 1 hypertension (BPs 140/90 mm Hg to 160/100 mm Hg) with diabetes or evidence of coronary heart disease.5 Were these recommendations inappropriate or do they represent a reasonable approach to treatment?

POSSIBLE ADVANTAGES OF COMBINATION THERAPY

  1. Top of page
  2. Abstract
  3. POSSIBLE ADVANTAGES OF COMBINATION THERAPY
  4. WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?
  5. WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?
  6. THE PROGRESS TRIAL
  7. THE ALLHAT TRIAL
  8. THE ANBP-2 TRIAL
  9. DIFFERENCES BETWEEN ALLHAT AND ANBP-2
  10. THE CONVINCE TRIAL
  11. RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY
  12. DRUG INTERACTIONS
  13. NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY
  14. TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?
  15. QUESTIONS AND ANSWERS
  16. References

When a combination of two different drugs with different mechanisms of action is used, BP response is greater and the percentage of responders to goal pressure is higher6,7 (Table IV). Titration to an effective dose is easier than increasing doses of single drugs. This may not appear to be important, but consider the patient's reaction during the process of titration of medication. If a physician believes in sequential monotherapy, he/she may try drug A on the initial visit. The dosage is increased on the second visit if there is no response. If drug A doesn't work, drug B may be tried. In another month, the dosage of this drug has to be increased. Several visits and considerable time may be taken to achieve goal BPs or the doctor may just decide to settle for less than an ideal result if the first two choices don't work. Contrast this to a physician who decides to use combination therapy initially, that is, a diuretic and another medication. The statistical odds are that 70% or more of patients will respond to the first dose of the medication. The perception of the patient is that the physician must be good. He or she got it right the first time. Another patient perception is also important—“I'm on one tablet instead of two or two instead of four; I must not be too ill.” Also, many hypertensives, for example, are on many pills per day for diabetes, arthritis, and other conditions. The fewer pills that are added the better chance that they will be taken.

Table IV.  Possible Advantages of Low-Dose Combination Therapy Compared With High-Dose Monotherapy
Blood pressure response is greater
Percentage of responders is higher
Side effects may be less
Titration to effective dose is simplified
Adherence is improved

WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?

  1. Top of page
  2. Abstract
  3. POSSIBLE ADVANTAGES OF COMBINATION THERAPY
  4. WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?
  5. WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?
  6. THE PROGRESS TRIAL
  7. THE ALLHAT TRIAL
  8. THE ANBP-2 TRIAL
  9. DIFFERENCES BETWEEN ALLHAT AND ANBP-2
  10. THE CONVINCE TRIAL
  11. RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY
  12. DRUG INTERACTIONS
  13. NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY
  14. TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?
  15. QUESTIONS AND ANSWERS
  16. References

Figure 1 describes a study with a low-dose cardio-selective β blocker, bisoprolol, in combination with only 6.25 mg hydrochlorothiazide. Usually when 6.25 mg hydrochlorothiazide is used as monotherapy, only about 15%–20% of people will respond. On the other hand, only about 20%–30% of people respond to a 2.5- or 5-mg dose of bisoprolol alone. When you combine these two agents in small doses, over 70% respond. Response is better than with adequate doses of amlodipine or enalapril. Figure 2 illustrates the effect of a diuretic when added to an ARB (losartan). BP decreases by an additional 10 mm Hg and diastolic Systolic BP decreases by an additional 4 mm Hg when a thiazide is given with losartan.

image

Figure 1. Blood pressure control rates with low-dose β blocker I diuretic combination compared with monotherapy with other agents; DBP=diastolic blood pressure; HCTZ=hydrochlorothiazide; p=0.002 vs. placebo; p=0.075 vs. amlodipine; p=0.001 vs. enalapril

image

Figure 2. Effect oflosartan or losartan/hydrochlorothiazide (HCTZ) on blood pressures. SBP=systolic blood pressure; DBP=diastolic blood pressure *pleqslant R: less-than-or-eq, slant0.01 vs. placebo; pleqslant R: less-than-or-eq, slant0.02 vs. losartan

Combination therapy also tends to do away with differences in responses in various racial groups. There is evidence that black patients do not respond as well to ACE inhibitors or ARBs as white patients. There is a clear benefit of combining a medication like a thiazide with one of the agents that block or decrease the activity of the renin-angiotensin-aldosterone system. In black patients on losartan, an angiotensin type 1 receptor blocker, for example, there is some BP response compared to placebo. When hydrochlorothiazide is combined with losartan, however, a more dramatic response is noted than with either drug alone. All racial differences in response rate disappear when other ARBs like irbesartan or ACE inhibitors like enalapril are given with a thiazide diuretic.

A combination of an ACE inhibitor and a CCB is also effective. For example, the combination of benazepril and amlodipine lowers BP to a greater extent than amlodipine or benazepril as monotherapy (Figure 3). Some data suggest that better results are obtained with combinations that include a thiazide diuretic than with medications that do not include the diuretic8 (Figure 4). Thus, with some exceptions, if a combination is going to be used, it should usually include a thiazide diuretic component.

image

Figure 3. Angiotensin-converting enzyme/calcium channel blocker combination; DBP=diastolic blood pressure

image

Figure 4. Percentage response (systolic blood pressure [BP] <140 mm Hg, diastolic BP <90 mm Hg) on combination therapy with two drugs that either do or do not include hydrochlorothiazide (HCTZ), for example captopril + diltiazem or captopril + diuretic. Adapted from Am J Hypertens. 1996;9(12 pt 2):187S–191S8

There are many combination medications available—(β blockers/diuretics, ACE inhibitors/diuretics, ARBs/diuretics, and CCBs/ACE inhibitors. There is a myriad of choices9 (Table V). In a patient who is at high risk or has stage 2 hypertension (BP geqslant R: gt-or-equal, slanted160/100 mm Hg), the use of two medications, one of which should usually be a diuretic, may often be the initial approach of choice.

Table V.  Some Examples of Combination Drugs for Hypertension
β Blocker+ DiureticACE-I + DiureticARB + DiureticCCB + ACE-I
CorzideCapozideDiovan HCTLexxell
Inderide LALotensin HCTHyzaarLotrel
Lopressor HCTPrinzideAvalideTarka
TenoreticVasereticAtacand HCT 
ZiacZesteretic  
ACE-I=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor blocker; CCB=calcium channel blocker

WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?

  1. Top of page
  2. Abstract
  3. POSSIBLE ADVANTAGES OF COMBINATION THERAPY
  4. WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?
  5. WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?
  6. THE PROGRESS TRIAL
  7. THE ALLHAT TRIAL
  8. THE ANBP-2 TRIAL
  9. DIFFERENCES BETWEEN ALLHAT AND ANBP-2
  10. THE CONVINCE TRIAL
  11. RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY
  12. DRUG INTERACTIONS
  13. NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY
  14. TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?
  15. QUESTIONS AND ANSWERS
  16. References

None of the clinical trials over the past 15 years have actually been trials of monotherapy. For example, a recent study, the Losartan Intervention for End-point Reduction in Hypertension (LIFE) study, reported that losartan proved to be more effective than atenolol in reducing overall cardiovascular events, especially stroke, in hypertensive patients with left ventricular hypertrophy,10 (Table VI) but only 10% of the patients had remained on the monotherapy, either of the ARB or the β blocker. More than 90% of patients required multiple medications to achieve goal BP. The BPs in the two groups were similar at the end of the trial. The study was thus a comparison of losartan plus other drugs, mostly thiazides, to atenolol with other drugs, mostly thiazides. The message was clear—losartan may have had an advantage over atenolol, but monotherapy had not proved effective in lowering BP to target levels.

Table VI.  Results of an ARB-Based (Losartan) Compared With a β Blocker-Based (Atenolol) Treatment Program in Hypertensive Patients With Left Ventricular Hypertrophy (LIFE Study)
 LosartanAtenololGoal BP
Achieved BP144/82 mm Hg145/82 mm Hg45%–50% SBP <140; 89% DBP <90
Primary end pointPercent Difference Losartan vs. Atenolol p Value
CV death, MI, stroke−13*0.02
Stroke−25*0.001
MI+07NS
CV mortality−11NS
Total mortality−10NS
New onset diabetes−25*0.001
ARB=angiotensin II receptor blocker; BP=blood pressure; SBP=systolic blood pressure; DBP=diastolic blood pressure; CV=cardiovascular; MI=myocardial infarction; NS=not significant; *statistically significant

Another example: The captopril study in type 1 diabetes and renal disease is presented as a captopril vs. placebo trial.11 A large number of patients in the captopril group received other drugs and the so-called placebo group received several different medications. The message for practicing physicians originally was that in a patient with type 1 diabetes, the use of captopril will delay or prevent progression of renal disease. The message should have been that captopril provided a benefit but other medications (a captopril-based treatment program) were necessary to reduce BP to achieve beneficial results.

In the Irbesartan Diabetic Nephropathy (IDNT) study in type 2 diabetics, patients who received irbesartan, an ARB, experienced less progression of renal disease than those on placebo or amlodipine12 (Table VII and Table VIII). Here again, the data showed that 31% of irbesartan patients were on thiazides, 67% were receiving loop diuretics, and 43% were receiving β blockers. The placebo group was receiving different drugs, and the third group in the study was receiving amlodipine (plus other medications). Irbesartan, in addition to other drugs, proved to be more effective than amlodipine or other medications in slowing the progression of renal disease in these type 2 diabetics. The IDNT study did not report that irbesartan monotherapy prevented renal disease progression in diabetic patients. The message should be that irbesartan, in addition to other drugs, proved to be more effective than other combinations. Blood pressure is not going to be lowered to goal levels with one medication in most patients with renal disease. The placebo designation in these trials indicates the use of medication other than the study drug but not a true placebo group.

Table VII.  Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients With Nephropathy Due to Type 2 Diabetes (IDNT) Trial
Percentage of Patients Who Received Medications in Addition to Study Drugs
 With IrbesartanWith Amlodipine**With Placebo*
Thiazide diuretics313435
Loop diuretics677371
Angiotensin-converting enzyme inhibitors697
Beta blockers434052
Calcium channel blockers798
Central adrenergic agonists353040
*Average of 3.3 nonstudy prescriptions; **average of 3.0 nonstudy prescriptions
Table VIII.  The Irbesartan Diabetic Nephropathy Trial (IDNT)*
No. of patients1715
Age30–70 years
Follow-up2.6 years
Baseline creatinine1.7 mg/dL
Proteinuria>900 mg/d
Results: 
Risk of renal disease progression decreased by 50%
Progression to dialysis or transplantation decreased by 26% compared to control or 34% compared to amlodipine-based treatment groups
The use of irbesartan, an A-II receptor blocker, decreased progression of renal disease and doubling of creatinine compared to a CCB (amlodipine) or other antihypertensive medication regimens
A-II=angiotensin II; CCB=calcium channel blocker; *INDT was a comparative study of an irbesartan vs. an amlodipine-based program or a control group on other antihypertensive medications. Adapted from N Engl J Med. 2001;345:851–860.12

In the Reduction in Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study, the use of an ARB, losartan, significantly slowed down progression of renal disease (Figure 5) and significantly reduced the occurence of end-stage renal disease, but again this was a study of an ARB plus other medications, most often a diuretic.13 The placebo group included other medications but not an ARB. The message again is clear—some medications have some specific effects but must usually be combined with other agents to reach therapy goals. If results are not as good in individual practices as they are in the clinical trials, one reason may be that multiple therapies are not being used as often.

image

Figure 5. Percentage of type 2 diabetic patients with end-stage renal disease in the Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy (RENAAL) study. Losartan group received therapy with angiotensin receptor blocker or other medications; placebo group received therapy with medications other than angiotensin receptor blocker or angiotensin-converting enzyme inhibitor (risk reduction, 28%; p=0.02). Dotted line=other medication; solid line=losartan. Adapted from N Engl J Med. 2001;345:861–869.13

THE PROGRESS TRIAL

  1. Top of page
  2. Abstract
  3. POSSIBLE ADVANTAGES OF COMBINATION THERAPY
  4. WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?
  5. WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?
  6. THE PROGRESS TRIAL
  7. THE ALLHAT TRIAL
  8. THE ANBP-2 TRIAL
  9. DIFFERENCES BETWEEN ALLHAT AND ANBP-2
  10. THE CONVINCE TRIAL
  11. RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY
  12. DRUG INTERACTIONS
  13. NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY
  14. TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?
  15. QUESTIONS AND ANSWERS
  16. References

A recent study, The Perindopril Protection Against Recurrent Stroke (PROGRESS) trial, attempted to answer the question, “When a patient has had a stroke, are recurrent strokes prevented if blood pressure is lowered?” For many years investigators believed that lowering BP in someone with a history of a stroke was not beneficial in preventing recurrent episodes, but in previous trials fewer than 40% of patients had had their BP lowered.

This trial showed than an ACE inhibitor/diuretic combination reduced recurrent strokes compared with results with medications other than an ACE inhibitor.14 In this trial, which had an ACE inhibitor arm and an ACE inhibitor/diuretic arm, the ACE inhibitor alone failed to influence outcome. The ACE inhibitor/diuretic combination did, however, prove to be effective in reducing events (Figure 6)—another example of the benefits of combination therapy.

image

Figure 6. Stroke risk reduction in patients treated with angiotensin-converting enzyme (ACE) inhibitor/diuretic compared with patients taking other medications (risk reduction, 28%; p<0.0001). Adapted from Lancet. 2001;358:1033–1041.14

THE ALLHAT TRIAL

  1. Top of page
  2. Abstract
  3. POSSIBLE ADVANTAGES OF COMBINATION THERAPY
  4. WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?
  5. WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?
  6. THE PROGRESS TRIAL
  7. THE ALLHAT TRIAL
  8. THE ANBP-2 TRIAL
  9. DIFFERENCES BETWEEN ALLHAT AND ANBP-2
  10. THE CONVINCE TRIAL
  11. RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY
  12. DRUG INTERACTIONS
  13. NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY
  14. TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?
  15. QUESTIONS AND ANSWERS
  16. References

In the Antihypertensive Therapy and Lipid-Lowering Heart Attack (ALLHAT) trial, therapies included a comparison of chlorthalidone, a thiazide diuretic, to amlodipine, a CCB, lisinopril, an ACE inhibitor, or doxazosin, an α blocker. This last comparison was discontinued because of disappointing outcome results with doxazosin compared with the diuretic. Amlodipine was titrated up to 10 mg/d and lisinopril up to 40 mg/d.

Add-on agents included reserpine, clonidine, a β blocker, or hydralazine. At the end of 5 years in the chlorthalidone and amlodipine groups, 40% of the patients were on step 2 and step 3 drugs. More than 40% in the lisinopril group were receiving multiple agents. ALLHAT was therefore a study of multiple drugs (Figure 7). At the end of 5 years the diureticbased group proved to be as good as or, in some situations, more effective than the other drugs in reducing certain cardiovascular events.15,16

image

Figure 7. Percent of patients who received step 2 or step 3 medication in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Chlor=chlorthalidone; Aml=amlodipine; Lis=lisinopril Adapted from JAMA. 2002;288:2981–2987.15

ALLHAT results indicated that a thiazide diuretic should be the first-step drug of choice in most cases. For about 40 years I have been one of the major supporters of diuretics, believing that the metabolic changes that may occur with these agents do not negate the benefits of their use in reducing morbidity/mortality in both nondiabetic and diabetic hypertensives. The ALLHAT study appears to confirm this, but ALLHAT also confirmed what has been known for many years—most hypertensive patients require more than one drug to reach goal BP levels; one of these should be a diuretic.17

THE ANBP-2 TRIAL

  1. Top of page
  2. Abstract
  3. POSSIBLE ADVANTAGES OF COMBINATION THERAPY
  4. WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?
  5. WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?
  6. THE PROGRESS TRIAL
  7. THE ALLHAT TRIAL
  8. THE ANBP-2 TRIAL
  9. DIFFERENCES BETWEEN ALLHAT AND ANBP-2
  10. THE CONVINCE TRIAL
  11. RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY
  12. DRUG INTERACTIONS
  13. NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY
  14. TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?
  15. QUESTIONS AND ANSWERS
  16. References

The Australian National Blood Pressure-2 (ANBP-2) trial, the other recent trial that has been widely publicized, reported that an ACE inhibitor proved to be marginally more effective (in men) than a diuretic in reducing cardiovascular events. Here too, the study was not a comparative monotherapy trial. In both the ACE inhibitor and thiazide arms of the study, multiple drugs were used.18

Blood pressure reductions were similar in the ANBP study with the ACE inhibitor-based program and the diuretic-based regimen, but specific medication use was of interest. At randomization, about 83% of people were on the allocated drug. At the end of the study only about 60% of people were on the randomized drug (ACE inhibitor or diuretic) (Table IX). Fewer than 40% were on monotherapy. The conclusion is that the Australian study, like the ALLHAT,16 LIFE,10 RENAAL,13 and IDNT12 studies, was a multiple drug trial.

Table IX.  Comparison of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and Australian Blood Pressure Study 2
 Allhat (blinded)Australian (Open Label)
No.24,3096083
Age6772
Black patients35%5%
Diabetics36%8%
Entry BP146/84168/91
 ACE-IDiureticACE-IDiuretic
Percent on study drug at 4+ years73%81%58%60%
Percent on study drug as monotherapy59%57%38%42%
Baseline146/84 mm Hg146/84 mm Hg168/91 mm Hg168/91 mm Hg
Final BP134/75 mm Hg136/75 mm Hg142/79 mm Hg142/79 mm Hg
ACE-I=angiotensin-converting enzyme inhibitor; BP=blood pressure

DIFFERENCES BETWEEN ALLHAT AND ANBP-2

  1. Top of page
  2. Abstract
  3. POSSIBLE ADVANTAGES OF COMBINATION THERAPY
  4. WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?
  5. WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?
  6. THE PROGRESS TRIAL
  7. THE ALLHAT TRIAL
  8. THE ANBP-2 TRIAL
  9. DIFFERENCES BETWEEN ALLHAT AND ANBP-2
  10. THE CONVINCE TRIAL
  11. RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY
  12. DRUG INTERACTIONS
  13. NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY
  14. TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?
  15. QUESTIONS AND ANSWERS
  16. References

The ALLHAT study was blinded. This can make a major difference in adherence to medication. For example, if a physician knows that a patient is receiving an ACE inhibitor and complains of a cough, the tendency might be to stop the medication. If, however, a study is blinded, he/she might wait for a week or two; perhaps the patient just had a cold or the flu. When an unblinded study, such as the Australian study, is conducted, changes in medications based on even minor side effects may be more common.

At the end of the ALLHAT study almost 60% of patients were still on monotherapy, but in the Australian study only about 40% were on the original medication (Table IX). Part of the “dropout” may have resulted from physicians' reactions to patients' complaints and knowledge of the medication being taken.

THE CONVINCE TRIAL

  1. Top of page
  2. Abstract
  3. POSSIBLE ADVANTAGES OF COMBINATION THERAPY
  4. WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?
  5. WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?
  6. THE PROGRESS TRIAL
  7. THE ALLHAT TRIAL
  8. THE ANBP-2 TRIAL
  9. DIFFERENCES BETWEEN ALLHAT AND ANBP-2
  10. THE CONVINCE TRIAL
  11. RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY
  12. DRUG INTERACTIONS
  13. NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY
  14. TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?
  15. QUESTIONS AND ANSWERS
  16. References

In another trial comparing a derivative of verapamil (Covera SR) to usual care (a diuretic/β-blocker regimen), the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) trial, a high percentage of patients on combination therapy achieved goal BP, but at the end of the trial 40% were on open-label medication. It is difficult to conclude anything about specific medication benefits in this trial.19

In the CONVINCE trial, where a modified form of verapumil was given at night and produced its maximum effect 4—6 hours later, it was hoped that the occurrence of cardiovascular events, which are more common between 6 a.m. and noon, would be less on this drug than other therapies. This was not noted. Events were similar during these hours in both groups of patients.

RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY

  1. Top of page
  2. Abstract
  3. POSSIBLE ADVANTAGES OF COMBINATION THERAPY
  4. WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?
  5. WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?
  6. THE PROGRESS TRIAL
  7. THE ALLHAT TRIAL
  8. THE ANBP-2 TRIAL
  9. DIFFERENCES BETWEEN ALLHAT AND ANBP-2
  10. THE CONVINCE TRIAL
  11. RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY
  12. DRUG INTERACTIONS
  13. NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY
  14. TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?
  15. QUESTIONS AND ANSWERS
  16. References

There are numerous causes of resistance in hypertension management. Some of these include: 1) doses of medication too low; 2) limited or inappropriate use of diuretics; and 3) inappropriate or too little use of multiple drugs or combinations. Despite data from the ALLHAT trial and many other studies, there are some physicians who are reluctant to use diuretics in treatment or, if they are used, they are given in doses that may not be effective. Concerns about the effects of diuretics on insulin resistance, cholesterol levels, sexual dysfunction, and potassium metabolism have been etched in the minds of many physicians to the point of ignoring good morbidity/mortality data. As noted, there may be some changes in glucose, cholesterol, and potassium levels, but these do not appear to be of clinical significance.20–22 It is also a fact that in carefully controlled studies over long periods of time sexual dysfunction is not greater on diuretics than on other drugs.

Another problem is in appropriate use of two drugs with similar actions. Patients should not be getting two different ARBs or ACE inhibitors, but some are. More of them should be receiving one of these agents along with a diuretic, with a third drug from a different class being added if goal BP is not achieved. The claim has been made that there is no additive effect when a diuretic is added to a CCB; however, our data and data from other investigators indicate an increased response rate when a CCB is added to a diuretic or a diuretic is added to a CCB. This can be a useful combination.23

NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY

  1. Top of page
  2. Abstract
  3. POSSIBLE ADVANTAGES OF COMBINATION THERAPY
  4. WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?
  5. WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?
  6. THE PROGRESS TRIAL
  7. THE ALLHAT TRIAL
  8. THE ANBP-2 TRIAL
  9. DIFFERENCES BETWEEN ALLHAT AND ANBP-2
  10. THE CONVINCE TRIAL
  11. RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY
  12. DRUG INTERACTIONS
  13. NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY
  14. TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?
  15. QUESTIONS AND ANSWERS
  16. References

The seventh JNC report5 and other national organizations recommend that patients with diabetes with or without renal disease, manifest either by a creatinine level of >1.5 mg/dL or proteinuria (more than 300 mg/d or +1 or more on a routine dipstick), will require at least two or three drugs to reach goal BP levels. This is also true in hypertensive diabetic patients with micro-proteinuria (about 30–300 mg/d). This is detected by a special dipstick test (Micral) that should be used more frequently. A majority of patients will achieve goal BPs with appropriate doses of two medications.

What about the initial use of two drugs separately or in combination in patients with stage 1 hypertension (140/90 mm Hg to 160/100 mm Hg)? When is this indicated? This can be considered if the patient is at high risk. For example, a patient with a consistent BP of 150/95 mm Hg with diabetes, an obese smoker, or someone with marked hyperlipidemia and a family history of cardiovascular disease may be a candidate for initial combination drug therapy.

Either a thiazide diuretic/ACE inhibitor, a thiazide diuretic/ARB, a thiazide diuretic/β blocker, or in some cases a thiazide diuretic/CCB or a CCB/ACE inhibitor combination is appropriate. These combinations in relatively small doses produce relatively few side effects.

Stage 2 hypertension (>160/100 mm Hg) may be a more specific indication to begin therapy with two medications. Two drugs will probably be needed to get these patients to goal levels. Why not start this therapy initially? Response rates will improve if this approach is taken. The clinical trials have indicated that more than one medication is necessary in these patients. The message is clear—therapy with combinations is more effective than higher dose monotherapy.

TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?

  1. Top of page
  2. Abstract
  3. POSSIBLE ADVANTAGES OF COMBINATION THERAPY
  4. WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?
  5. WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?
  6. THE PROGRESS TRIAL
  7. THE ALLHAT TRIAL
  8. THE ANBP-2 TRIAL
  9. DIFFERENCES BETWEEN ALLHAT AND ANBP-2
  10. THE CONVINCE TRIAL
  11. RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY
  12. DRUG INTERACTIONS
  13. NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY
  14. TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?
  15. QUESTIONS AND ANSWERS
  16. References

Recommendations regarding goal BPs in the elderly are to reduce systolic BP to <140 mm Hg. This is often difficult to achieve. For example, when pressures are reduced from 180 or 170 mm Hg to about 155 or 160 mm Hg, the patient may not feel well—some fatigue, lightheadedness, and the like. If the national recommendations are followed and medication is progressively increased, side effects often become quite annoying. The patient may stop all medication.

What is a reasonable approach? Reduce BP in stages.24 A decrease of only about 12–15 mm Hg systolic may decrease events. In the Systolic Hypertension in the Elderly (SHEP) study,25 for example, that is how much BP was lowered compared with placebo—with a significant reduction in morbidity/mortality. If a patient feels fatigued, faint, or tired when BP is reduced from 180 to 160 mm Hg, keep him/her on the same dosage or reduce it to some degree, but do not increase it. Wait 4–6 weeks to allow the baroreceptors to be reset. When the patient begins to feel better, increase the medication or add another drug and hope to reduce BP still further without producing annoying symptoms. Although guidelines stress that BPs in the elderly should be lowered to a systolic BP <140 mm Hg, this may not be possible in some patients even with the appropriate use of two different medications.

The number of people controlled at goal levels of <140/90 mm Hg today is about 35%. It should be closer to 60%—not 100%—but closer to 60%. More patients will be controlled if combination therapy is used more frequently. If this can be done, morbidity/mortality will be reduced.

QUESTIONS AND ANSWERS

  1. Top of page
  2. Abstract
  3. POSSIBLE ADVANTAGES OF COMBINATION THERAPY
  4. WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?
  5. WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?
  6. THE PROGRESS TRIAL
  7. THE ALLHAT TRIAL
  8. THE ANBP-2 TRIAL
  9. DIFFERENCES BETWEEN ALLHAT AND ANBP-2
  10. THE CONVINCE TRIAL
  11. RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY
  12. DRUG INTERACTIONS
  13. NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY
  14. TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?
  15. QUESTIONS AND ANSWERS
  16. References

Following the presentations there were many questions from the audience. Some of these included:

Question: Is there any place for the use of aldosterone antagonists in therapy?

Spironolactone, which is an aldosterone antagonist, was used for many years in patients with heart failure who were resistant to therapy because of secondary aldosteronism. We used it in hypertensive patients in combination with a thiazide diuretic as aldactazide. It was very effective, but side effects, especially gynecomastia in male patients, limited its use. A more selective aldosterone antagonist, eplerenone is presently available. This agent has fewer side effects.

Question: What happens if a patient stops taking medication after being normotensive for a year or so?

Within about 3–6 months, about 80% note a rise in BP. BPs may remain normotensive for months before beginning to increase. Good advice would be to suggest a decrease but not a cessation of medication in someone who had been normotensive for a long time. Reduce the dosage of one or, if the patient is on two or more drugs, each of the medications. Only a few patients will remain normotensive on the reduced dosage for longer than a few months. I do not believe medication should be stopped in the above situation.

Question: What do you do about white coat hypertension?

Let me give you a biased opinion. There are probably 15%–20% of patients who have “white coat hypertension,” that is, blood pressures are high in the office and normal at home. If physiologic studies are done on these patients, vascular resistance is shown to be increased, left ventricular diastolic dysfunction (one of the early signs of heart involvement) may be present, and many may have the metabolic syndrome that Dr. Izzo discusses in another section of this symposium.

I personally believe that white coat hypertension should be treated. Always balance benefit to risk. If we were still using ganglion blockers, peripheral blockers, or centrally acting agents like methyldopa that may cause syncope and central nervous system symptoms for example, it wouldn't be worth it, but we have medications now that are safe, easy to take, and relatively inexpensive. The benefit, I believe, outweighs the risk. Of course, if a white coat hypertensive responds to lifestyle changes, he/she doesn't need medication.

Question: What about ambulatory blood pressure monitoring (ABPM)?

None of the JNC reports suggest ABPM as a routine part of the initial workup. It is helpful in determining the duration of action of a drug and in the evaluation of a new drug it is quite useful. Occasionally ABPM will help clarify a clinical problem. For example, is the symptom secondary to low or high BP? The situation might be clarified by ABPM in someone who is dizzy or has headaches at home and doesn't have a record of home BPs at that time. There are few indications I know of where ABPM is going to change what you do in practice.

There is a great deal in the literature advocating wider use of ABPM. It is reflective of target organ involvement, but I really believe you can treat patients effectively without it.

Question: If you did treat a white coat hypertensive with an office pressure of about 150–155/90–95 mm Hg, would you use monotherapy?

Monotherapy in a white coat hypertensive is quite appropriate because he/she will probably respond. Young white patients will respond to a β blocker in small doses. If the patient is older or black, small doses of a diuretic or a CCB are appropriate. I would not start combinations in those people.

Question: Should an echocardiogram be obtained in these patients?

An echocardiogram will demonstrate left ventricle dysfunction, left atrial enlargement, or some left ventricle enlargement if it is present. In these instances it would be clear that the patient should be treated, even with normal home BPs, but I do not believe this test is routinely necessary. Data indicate that white coat hypertensives eventually will develop persistent hypertension; they should be treated regardless of echocardiographic findings. Years ago a follow-up of Army recruits who had transient hypertension showed that these transient BP elevations were predictive of the future.

Question: Have there been good studies with ACE inhibitors and diuretics in type 2 diabetes that demonstrate slowing of progression of kidney disease?

Currently there are none, but if I were to guess I would say that if a study were done in type 2 diabetics with an ACE inhibitor/diuretic, we probably would see a slowing down of progression of renal disease just as has been noted in studies with ARBs and diuretics.

References

  1. Top of page
  2. Abstract
  3. POSSIBLE ADVANTAGES OF COMBINATION THERAPY
  4. WHAT ARE SOME OF THE DATA WITH VARIOUS COMBINATIONS?
  5. WHAT HAVE THE CLINICAL TRIALS REPORTED ABOUT COMBINATION OR MULTIPLE-DRUG THERAPY?
  6. THE PROGRESS TRIAL
  7. THE ALLHAT TRIAL
  8. THE ANBP-2 TRIAL
  9. DIFFERENCES BETWEEN ALLHAT AND ANBP-2
  10. THE CONVINCE TRIAL
  11. RESISTANT HYPERTENSION—A MAJOR CAUSE MAY BE THE LACK OF USE OF MULTIPLE OR COMBINATION THERAPY
  12. DRUG INTERACTIONS
  13. NEW NATIONAL RECOMMENDATIONS FOR COMBINATION-DRUG THERAPY
  14. TREATMENT OF THE ELDERLY—WHAT ABOUT THE USE OF MORE THAN ONE MEDICATION IN THESE PATIENTS?
  15. QUESTIONS AND ANSWERS
  16. References
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  • 23
    Frishman WH, Zawada ET, Smith LK, et al. Comparison of hydrochlorothiazide and sustained-release diltiazem for mild-tomoderate systemic hypertension. Am J Cardiol. 1987;59:615623.
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