Letters to the Editor

Antihypertensive Treatment and CHD in the Elderly



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Am Fam Physician. 1999 Sep 15;60(4):1102-1104.

to the editor: In a recent review1 on antihypertensive pharmacotherapy in the elderly, Dr. Moser commented briefly on the treatment of patients with concomitant diabetes mellitus. He reiterated the greater benefits of blood pressure reduction in patients with diabetes, citing both the Hypertension Optimal Treatment (HOT) trial2 and the European Trial on Systolic Hypertension Study in the Elderly (Syst-Eur).3 Both of these studies used dihydropyridine calcium channel blockers as first-line agents. However, the evidence is conflicting regarding the choice of calcium channel blockers as initial treatment of hypertension in patients with diabetes.

The double-blinded HOT trial2 randomized 1,501 patients with diabetes into three different groups according to target diastolic blood pressure. At the end of the study, only 9 percent of patients in the treatment groups were still taking felodipine alone. A non-significant trend was demonstrated toward lower rates of myocardial infarction and lower diastolic blood pressures in patients with diabetes. Data comparing the outcomes of the treatment and control groups were not available.

Syst-Eur,3 a randomized double-blind trial, also compared a dihydropyridine calcium channel blocker, nitrendipine, with placebo. Fifty-five percent of the patients with type 1 (formerly known as insulin-dependent) and type 2 (formerly known as non–insulin-dependent) diabetes mellitus were taking nitrendipine alone at the end of the study. The authors found a 57 percent reduction in cardiac events among diabetic patients in the treatment group, compared with patients in the placebo group.

Two studies, the Appropriate Blood Pressure Control in Diabetes (ABCD)4 trial and the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET),5 were not mentioned in Dr. Moser's article. Both studies compared a dihydropyridine calcium channel blocker with an angiotensin-converting enzyme (ACE) inhibitor in patients with type 2 diabetes (nisoldipine and enalapril in the ABCD trial). Of the 470 diabetic patients in the ABCD trial, the group treated with nisoldipine had a significantly higher number of fatal or nonfatal myocardial infarctions compared with the group treated with enalapril. Of the 380 diabetic patients enrolled in FACET, 5 the group treated with fosinopril had a lower number of fatal or non-fatal myocardial infarctions compared with the group treated with amlodipine. Although this difference was not significant, the number of major vascular events in the amlodipine group compared with the fosinopril group was significant.

These studies raise questions about the role of dihydropyridine calcium channel blockers in treating hypertension in diabetic patients. Since only 9 percent of patients were taking the calcium channel blocker alone in the HOT trial, 2 the benefits may instead be related to the other medications; the findings in Syst-Eur were not statistically significant. The evidence presented in both the ABCD4 and FACET5 trials supports using ACE inhibitors rather than calcium channel blockers as initial antihypertensive medications in diabetic patients, particularly in those with type 2 diabetes. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),6 which is studying amlodipine, lisinopril, doxazosin and chlorthalidone, will provide additional useful information.

Dr. Ellsworth has received honorariums from Merck and Novartis.

REFERENCES

1. Moser M. Hypertension treatment and the prevention of coronary heart disease in the elderly. Am Fam Physician. 1999;59:1248–56.

2. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755–62.

3. Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R, Bulpitt CJ, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Systolic Hypertension in Europe Trial Investigators. N Engl J Med. 1999;340:677–84.

4. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998;338:645–52.

5. Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G, et al. Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21:597–603.

6. Davis BR, Cutler JA, Gordon DJ, Furberg CD, Wright JT Jr, Cushman WC, et al. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Research Group. Am J Hypertens. 1996;9(4 Pt 1):342–60.

in reply: Drs. Fink and Ellsworth made some interesting comments, but they may have misinterpreted some of the material in our paper.

In reference to the benefits of blood pressure reduction in patients with diabetes, the SHEP study1 was cited as having achieved benefit with a diuretic-based treatment program whether or not the patient had diabetes mellitus. In fact, as noted, diabetic patients did better in terms of reduction of cardiac events than the patients who were not diabetic. In the HOT study,2 in which a calcium channel blocker was used as initial therapy, the patients who achieved the lowest blood pressures, that is, the group with diastolic pressures in the below 80 mm Hg target group, appeared to have some additional benefit if they were in the cohort of patients with diabetes. We did not specifically highlight the Syst-Eur study,3 which used a dihydropyridine, nitrendipine, as initial therapy. In this study, as Drs. Fink and Ellsworth noted, a nonstatistically significant decrease occurred in coronary heart disease events in the treated group, compared with the placebo group.

Although the Syst-Eur3 and HOT2 studies used calcium channel blockers as initial treatment, a majority of the patients, especially those in the HOT study, were taking at least two or three different medications at the end of the trial. We did not suggest that the use of a calcium channel blocker specifically reduced coronary heart disease events. In fact, it was clearly pointed out that in the Syst-Eur study, no statistically significant reduction in myocardial infarction was achieved compared with the SHEP trial.1 This, of course, may have been secondary to the short duration of the trial. The HOT study did not include a control group. As noted, this was a study comparing levels of blood pressure achieved rather than a comparison between treated and untreated patients.

The ABCD4 and FACET5 studies were not reviewed because these were small studies and did not specifically target elderly patients. For this reason these studies were not mentioned in our paper. Drs. Fink and Ellsworth are correct that in both of these trials the use of an angiotensin-converting enzyme (ACE) inhibitor appeared to produce fewer coronary heart disease events than the use of a calcium channel blocker.

I agree with Drs. Fink and Ellsworth that in any patient with diabetes, elderly or not, the ideal therapy probably is an ACE inhibitor or an angiotensin II receptor blocker with a diuretic. However, the recent UKPKS study6 in patients with type 2 diabetes reported that a significant reduction in coronary heart disease events was noted in patients with tight blood pressure control (achievable blood pressure of 144/82 mm Hg compared with 154/87 mm Hg, a difference of -10/-5). No difference in outcome was apparent between the group taking a beta blocker and a diuretic and the group taking an ACE inhibitor and a diuretic. Again, this was not a study of elderly patients.

The major point of our paper was that lowering the blood pressure in elderly patients, whether or not they have isolated systolic or systolic/diastolic hypertension, will reduce coronary heart disease events, especially in patients at high risk, such as diabetic patients. I trust that this will answer some of Dr. Fink's and Dr. Ellsworth's queries.

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). JAMA. 1991;265:3255–64.

2. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the hypertension optimal treatment (HOT) randomised trial. Lancet. 1998;351:1755–62.

3. Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R, Bulpitt CJ, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Systolic Hypertension in Europe Trial Investigators. N Engl J Med. 1999;340:677–84.

4. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998;338:645–52.

5. Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G, et al. Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21:597–603.

6. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703–13.

Send letters to Kenneth W. Lin, MD, MPH, Associate Deputy Editor for AFP Online, e-mail: afplet@aafp.org, or 11400 Tomahawk Creek Pkwy., Leawood, KS 66211-2680.

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