Special Report
By Harold L. Karpman, MD, Clinical Professor of Medicine, UCLA School of Medicine; Associate Editor, Internal Medicine Alert.
Several classes of pharmacological agents have demonstrated benefits in hypertensive patients with CAD, but most published studies have, of necessity, enrolled only patients with an elevated or borderline elevated blood pressure. Recent clinical trials have demonstrated benefits for both angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCB) in patients with coronary artery disease (CAD) with relatively normal or borderline elevated blood pressures. However, few studies have specifically targeted patients with angiographically documented coronary artery obstructions and normal blood pressures.1-3 Because of the aging population and the increasing prevalence of diabetes, obesity, and lack of exercise, the number of persons with CAD is dramatically increasing and, therefore, it has become critically important for us to acquire prospective, randomized, trial data on the relative impact of various drugs and blood pressure levels on adverse outcomes in patients with CAD.
Dr. Steven Nissen and his colleagues from The Cleveland Clinic studied the effects of amlodipine and enalapril on cardiovascular events and atherosclerosis progression in 1991 patients with angiographically documented CAD in a carefully performed double-blind, randomized, multicenter, 24-month trial.4 Patients with CAD and treated blood pressure within the normal range (< 140 mm Hg) were randomly assigned to receive a placebo, a CCB (amlodipine), or an ACE inhibitor (enalapril). Compared with placebo, amlodipine and enalapril reduced blood pressure similarly (approximately 5 mm Hg systolic) when added to beta blockers with or without diuretics. The patients assigned to amlodipine who had an average baseline systolic blood pressure of 129/78 mm Hg experienced a 5/3 mm Hg blood pressure reduction, a 31% relative reduction in adverse cardiovascular events (ie, hospital admissions for angina, coronary revascularizations) and demonstrated a trend toward reduced death, MI, and stroke. The enalapril group had a minimal blood pressure reduction (5/2 mm Hg) but also demonstrated a statistically nonsignificant 15.3% relative reduction in adverse cardiovascular events. An intravascular ultrasound (IVUS) sub study at 38 sites revealed a trend toward less progression of atherosclerosis in the amlodipine group vs the placebo group with significantly less progression in the subgroup with systolic blood pressures greater than the mean. Compared with baseline, IVUS showed significant progression in the placebo group, a trend toward progression in the enalapril group, and no progression in the amlodipine group.
The age-specific increase in risk for CAD mortality associated with usual blood pressures is continuous for systolic blood pressures > 115 mm Hg (ie, the absolute risk for CAD death in 50-59 year-old patients is approximately 3 at a systolic blood pressure of 120 mm Hg, about 8 at 140 mm Hg, and exceeds 30 for 180 mm Hg or higher).5 This observation would suggest that the management of blood pressure is similar to the current management of LDL cholesterol (ie, lower is better) however, the physiological effects of blood pressure management are more complex because the distribution of systolic and diastolic blood pressures is continuous and it is difficult to the identify the "normal" blood pressure for any specific individual.6 Nissen et al made their important observations on patients with normal blood pressures who were on appropriate medical therapy (ie, high rates of statin and aspirin use). Their observations that amlodipine used for 24 months results in a 31% relative reduction in adverse cardiovascular outcomes and a significant decrease in the progression of IVUS-measured coronary atherosclerosis suggest that the optimal blood pressure range for patients with CAD may be substantially lower than recommended by current guidelines. Their conclusions are guarded because the sample size consisted of only 2000 patients and because the end points were relatively broad (ie, not the traditional somewhat more rigid end points of death, MI, and stroke).
In summary, the most intriguing result of this study in my mind is to again raise the increasingly asked question of what is the optimal target systolic blood pressure to prevent coronary atherosclerosis progression. The optimal blood pressure level in patients with CAD remains unclear; however, published data suggest that it is clearly lower then the commonly accepted 140 mm Hg range, and more probably is in the 120 mm Hg range.6,7 Multidrug strategies are usually needed to achieve lower blood pressure targets, especially in patients with diabetes and renal insufficiency, but the benefits appear to far outweigh the risks of these pharmaceutical agents and it now appears quite likely that the CAD population will also benefit substantially by dropping the currently accepted blood pressure guidelines to lower levels. The final answer to what is a normal blood pressure in the CAD population will have to await larger and perhaps longer-term studies of antihypertensive therapies but, for the time being, it would appear prudent to consider resetting the desired systolic blood pressure target range from 140 mm Hg to 120 mm Hg in those patients who can tolerate lower blood pressures without significant symptoms.
References
1. Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153.
2. Fox KM, et al. Lancet. 2003;362:782-788.
3. Pitt B, et al. Circulation. 2000;102:1503-1510.
4. Nissen, SE, et al. JAMA. 2004;292:2217-2226.
5. Prospective Studies Collaboration. Lancet. 2002;360: 1903-1913.
6. Elliott P. High blood pressure in the community. In: Bulpitt CJ, ed. Handbook of Hypertension. Amsterdam, the Netherlands: Elsevier Science;2000: 1-18.
7. Pepine CJ, et al. JAMA. 2003;290:2805-2816.
Several classes of pharmacological agents have demonstrated benefits in hypertensive patients with CAD, but most published studies have, of necessity, enrolled only patients with an elevated or borderline elevated blood pressure. Recent clinical trials have demonstrated benefits for both angiotensin-converting enzyme inhibitors and calcium channel blockers (in patients with coronary artery disease with relatively normal or borderline elevated blood pressures.
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