The Therapeutics Initiative is at arms length from government and other vested interest groups. Our function is unbiased review and dissemination of therapeutic evidence. Assessments apply to most patients; exceptional patients require exceptional approaches. We are committed to evaluate the effectiveness of our educational activities using the Pharmacare database without identifying individual physicians, pharmacies or patients.

Therapeutics Letter, issue 8, July/August 1995

Drugs of Choice in the Treatment of Hypertension

(Part 2)

After review of the long term hypertension studies, including the epidemiologic and randomized placebo controlled drug trials, certain clinically important facts stand out:

• Risk of cardiovascular events correlates better with systolic than diastolic blood pressure.(1)

• Risk correlates better with blood pressures taken outside the doctor's office than with office blood pressures.(2)

• Blood pressure consistently decreases with placebo treatment (10/8 mm Hg).(3)

• The average additional blood pressure fall in the active treatment group is modest (11/6 mm Hg).(3), (4)

• The average blood pressure fall with treatment in trials using low doses of just one drug (7-9.5/46.5mm Hg) (5), (6) is similar to that obtained from an overview of trials using high doses of multiple drugs (11/6 mm Hg).(3), (4)

 These facts suggest the following ways to assist in managing your patients with hypertension:

• Put more emphasis on systolic and home blood pressures when making treatment decisions.

• Appreciate that some of the blood pressure lowering effect seen in the office is due to the placebo effect. In other words, no matter what you are prescribing, it is likely to appear efficacious.

• Realize that pushing the dose seldom improves the antihypertensive effect. Likewise, the dose can frequently be lowered in patients receiving high doses of antihypertensive drugs without changing the antihypertensive effect.

In Part 1 we summarized the published evidence demonstrating that if we want to be certain of reducing morbidity and mortality in our hypertensive patients, a low-dose thiazide diuretic is the best choice. However, we obviously need the use of more than one class of antihypertensive drugs. Beyond the thiazides, we have much less evidence of effectiveness in decreasing cardiovascular events. We cannot assume that drugs which are equivalent in lowering blood pressure will prove to be equally effective in reducing morbidity and mortality.

What is the evidence that beta blockers decrease morbidity and mortality in hypertensive patients?

There are only two trials in which the effectiveness of beta blockers (propranolol(3) and atenolol(7)) can be compared with placebo. When the data from these trials are combined, there is a trend towards a reduction in the incidence of total stroke, log odds ratio, 0.77 (0.59-1.04), but little effect on total coronary events, 0.89 (0.71-1.13). The lack of effectiveness of atenolol based therapy in reducing coronary events corroborates that seen in other studies. (8), (9) It may be that the high cardioselectivity of atenolol is not a desirable pharmacological action.

There are three trials(3), (7), (10) in which the effectiveness of beta blockers can be compared with thiazides. When the results of these trials are combined in a meta-analysis the patients receiving thiazide had a non statistically significant reduction in the incidence of stroke, 0.81 (0.58-1.14)and coronary events, 0.92 (0.74-1.14). In post myocardial infarction trials, non-selective beta blockers and high dose beta-1 selective blockers, but not oxprenolol or pindolol, beta blockers with high partial agonist (increased sympathomimetic) activity, reduce risk of reinfarction and mortality.(11) With the evidence presently available, it is advisable when prescribing beta blockers to use a non-selective beta blocker in the lowest dose required to lower the blood pressure (see Table).

In what hypertensive patient is a beta blocker the drug of first choice?

To lower blood pressure in patients with angina pectoris a beta blocker is the drug of first choice. Although we do not have the evidence, it also seems reasonable to use a beta blocker as first choice in patients where the drug can be used to treat more than the hypertension, eg. patients with frequent recurrent migraine or patients with sympathetic hyperactivity, resting tachycardia, and palpitations. Beta blockers should not be used in patients with asthma or other forms of obstructive airways disease.

Table 1: Beta Blockers

* non-selective || º selective || ^ partial agonist || ª alpha blocker

(x) Average or lowest cost alternative (LCA) price in BC, 1994.

In what hypertensive patient is an ACE inhibitor the drug of first choice?

ACE inhibitors have been clearly shown to prolong survival in patients with congestive heart failure.(12) They are therefore the obvious first choice in patients with hypertension and CHF. It is not established at the present time whether ACE inhibitors have a unique renal protective effect in diabetic nephropathy.(13)

A recent study suggests that ACE inhibitors increase the risk of hypoglycemia in treated diabetic patients.(14) There are no proven therapeutic differences between the ACE inhibitors; drug choice can be made based on convenience and cost. (see Table). The cost can be minimized by prescribing 1/4 or 1/2 tablets whenever possible. (e.g.1/4 of a 20 or 40 mg tablet of quinapril costs $0.23 a day).

Table 2: ACE Inhibitors

(x) Average or lowest cost alternative (LCA) price in BC, 1994.

In what hypertensive patient is a calcium antagonist the drug of first choice?

At the present time there are no outcome studies which identify a group of patients who would specifically benefit from a calcium antagonist. It is clear that post MI patients with left ventricular dysfunction do worse with diltiazem than with placebo.(15) An overview of 31 placebo controlled trials submitted to the United States Food and Drug Administration (16) reported that patients receiving calcium antagonists had a 63% excess of cardiac events, as compared to placebo.

A recent unpublished but highly publicized study also suggests that patients receiving a calcium antagonist for hypertension have a significantly increased risk of myocardial infarction compared with patients receiving diuretics or beta blockers. Neither of these studies are definitive. They do, however, reinforce the message in this and the previous letter, and emphasize the need for prospective randomized controlled studies measuring morbidity and mortality. These trials are under way, but we cannot expect any results for 4 - 5 years.

Table 3: Calcium Antagonists

(x) Average or lowest cost alternative (LCA) price in BC, 1994.

In what hypertensive patients are second drugs useful?

From the large controlled studies of the treatment of mild hypertension it is clear that in at least 50% of patients the BP can be controlled with a thiazide alone. The additional drugs used in these studies, for patients not controlled with a thiazide include reserpine in three studies, methyldopa in two studies, hydralazine in two studies, and beta blockers in two studies. We thus can have some confidence in the effectiveness of these drugs used in combination with a thiazide. In patients with moderate to severe hypertension 3 to 4 drugs are often required to adequately control the blood pressure. We, therefore, are fortunate to have a wide armamentarium of drugs to choose from (see Tables).

Conclusion

It is up to the clinician, through systematic therapeutic trials, to identify the drug(s) which are efficacious, well tolerated in low doses, convenient, and affordable to the patient and society. We should use the drugs proven to reduce morbidity and mortality as much as possible, but occasionally we are forced to individualize and choose based on other factors.

Table 4: Alpha 1 Blockers

(x) Average or lowest cost alternative (LCA) price in BC, 1994.

Table 5: Central and Peripheral Sympatholytics

(x) Average or lowest cost alternative (LCA) price in BC, 1994.

Table 6: Direct Vasodilators

  * Average or lowest cost alternative (LCA) price in BC, 1994.

REFERENCES

1. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: Final results of the Systolic Hypertension in the Elderly Program (SHEP). J.Amer. Med Assoc. 1991;265:3255-64.

2. Verdecchia P, Porcellati C, Schillaci G, et al. Ambulatory Blood Pressure an independent predictor of prognosis in essential hypertension. Hypertension 1994;24:793-801.

3. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br.Med. J. 1985;291:97-104.

4. Collins R, Peto R, MacMahon S, et al. Epidemiology, blood pressure, stroke and coronary heart disease. Part 2: Short-term reductions in blood pressure: Overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827-38.

5. Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. N Engl J Med 1993;328:914-21.

6. Treatment of Mild Hypertension Study Research Group. Treatment of Mild Hypertension Study Final Results. JAMA 1993;270:713-724.

7. Medical Research Council trial of treatment of hypertension in older adults: Principal results. Br. Med. J. 1992;304:405-12.

8. Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care. Br. Med. J.1986;293:1145-1151.

9. Kaplan NM. Critical comments on recent literature. SCRAAPHY about MAPHY from HAPPHY. Amer J. Hypert. 1988;1:428-430.

10. HAPPHY Collaborative Group. Heart Attack Primary Prevention in Hypertensives (HAPPHY), J Clin Hypertens, 1987;5:561-572.

11. Yusuf S, Peto R, Lewis J, et al. Beta blockade during and after myocardial infarction: An overview of the randomized trials. Progress in Cardiovascular Disease, Vol XXVII, No.5, 1985:pp 335-371.

12. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995;273:1450-1456.

13. Bauer JH. Diabetic Nephropathy: Can it be prevented? Are there renal protective antihypertensive drugs of choice? South Med. J. 1994; 87:1043-1052.

14. Herings RMC, de Boer A, Stricker BHCh, et al. Hypoglycaemia associated with use of inhibitors of angiotensin converting enzyme inhibitors. Lancet 1995;345:1195-98.

15. The Multicentre Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988;319:385-92.

16. Glasser SP, Clark PI, Lipicky RJ et al. Exposing patients with chronic, stable, exertional angina to placebo periods in drug trials. J. Amer. Med. Assoc. 1991;265:1550-1554.

Please send feedback!

Back to Therapeutics Letter.

Back to the Therapeutics Initiative Home Page.

©Therapeutics Initiative. Last updated: November 25, 1996.