- Email: [email protected]
Systemic hypertension and coronary artery disease
Systemic Hypertension and Coronary Artery Disease Carl J. Pepine,
MD
In the United States alone, it is estimated that 60 million people have hypertension, the estimate varying according to whether hypertension is defined as a blood pressure of >140/90 mm Hg or, as has emerged from the Sixth Joint National Commission on Hypertension (JNC VI) consensus conference, of >130/90 mm Hg. Coronary artery disease frequently accompanies hypertension. In our studies of >5,000 patients with coronary artery disease, half had hypertension. The reasons are numerous. Hypertension is a major risk factor for CAD. The incidence of both conditions increases with age, so that the majority of individuals >65 years of age with
coronary artery disease probably also have hypertension. Some authorities predict that, due to the increasing size of the elderly population, there will be a doubling in the prevalence of both coronary artery disease and hypertension in the next century. This is of vital concern to all clinicians. This article reviews some of the prevalence and population trends in coronary artery disease and hypertension, and some of the pathogenic mechanisms involved, as well the results of some current outcome trials. Q1998 by Excerpta Medica, Inc. Am J Cardiol 1998;82:21H–24H
ypertension is a risk factor for angina. In our contemporary cohort study of 5,000 patients with H angina, half also had hypertension, and the frequency
THE IDEAL ANTI-ISCHEMIC/ ANTIHYPERTENSIVE AGENT
of both conditions increased with age.1 The Framingham study2 showed that the risk of all coronary artery disease complications is approximately doubled in the presence of hypertension. Hypertension is a major risk factor both for symptomatic and for “silent” or unrecognized myocardial infarction, for example. In the elderly, silent myocardial infarctions comprise a considerable proportion of the total; in the Framingham study, half or more of all myocardial infarctions in individuals aged .65 years were silent. These silent myocardial infarctions are clinically important because they carry the same long-term prognosis as recognized myocardial infarctions. Silent or unrecognized ischemic heart disease in hypertensive patients is particularly relevant to concerns about calcium antagonists,3 which are further discussed below. The risk of sudden death, heart failure, and all-cause mortality are also increased in hypertensive individuals.
PATHOPHYSIOLOGY Current evidence suggests that hypertension, via increased oxidant stress, damages endothelium. This evokes a number of responses that disrupt the balance between processes such as constriction/dilation, proliferation/antiproliferation, thrombosis/antithrombosis, and fibrinolysis/antifibrinolysis. These consequences of endothelial dysfunction may lead to transient ischemia (through hypoperfusion) or ischemiarelated adverse outcomes (coronary thrombosis, sudden death). From the Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida. Address for reprints: Carl J. Pepine, MD, Division of Cardiology, University of Florida College of Medicine, 1600 SW Archer Road, Box 100277, Gainesville, Florida 32610. ©1998 by Excerpta Medica, Inc. All rights reserved.
Based on these epidemiologic and pathophysiologic considerations, and on our understanding of vascular biology, the ideal anti-ischemic/antihypertensive agent should prevent ischemia-related outcomes (e.g., death and myocardial infarction). It should also: (1) restore vascular function and structure; (2) halt deterioration of endothelial function; (3) inhibit vasoconstriction, not only in the coronary circulation, but also in the renal and cerebral circulations; (4) improve left ventricular diastolic function and reverse or prevent left ventricular hypertrophy, if present; (5) have antithrombotic and profibrinolytic activity; (6) have antioxidant activity; (7) be well tolerated as a once-daily formulation; and (8) be safe in combination with other agents, because a single agent is often inadequate to manage patients with both ischemic heart disease and hypertension.
RETROSPECTIVE, CASE-CONTROLLED STUDIES OF CALCIUM ANTAGONISTS Calcium antagonists initially appeared as an attractive option for management of patients with ischemic heart disease and hypertension, and were frequently used for .20 years. Yet, as discussed elsewhere in this symposium,3 data on clinical outcome, specifically myocardial infarction and death, were lacking. The first case-controlled data appeared in 19954 and suggested that, in patients with presumably uncomplicated hypertension, treatment with various short-acting, first-generation calcium antagonists—as opposed to b blockers and diuretics—was associated with a 60% excess risk for adverse outcome. There were only 56 cases and 170 controls, and the confidence intervals were wide (e.g., 4 –239%). Yet another study,5 using the same methodology, reported that these same calcium antagonists, plus amlodipine, were associated with a decreased risk of adverse outcome of approximately 30% when compared with b blockers and diuretics. In this report, the diagnosis of acute myo0002-9149/98/$19.00 PII S0002-9149(98)00487-1
21H
cardial infarction was documented by in-hospital records; the data suggested a 10% reduction for acute myocardial infarction, but with wide confidence intervals. Three other reports (Aursnes et al,6 Leader et al,7 and Alderman et al8) also suggested a decrease in risk for myocardial infarction of approximately 37% (ranging from 24 –51%). Furthermore, the earlier study4 suggested approximately the same excess risks for myocardial infarction (;60%) in patients with and without pre-existing cardiovascular disease. Clearly these results are inconsistent with our current understanding of the mechanisms of action of these agents as well as the pathogenesis and outcomes of the diseases they are used to treat. These conflicting findings may be attributable to a number of methodologic shortcomings in these retrospective, case-controlled studies. In particular, there was no assessment of the control or the severity of the hypertension, or of the presence or severity of associated coronary artery disease, especially when in the form of an unrecognized myocardial infarction or ischemia. In addition, there was no assessment of patient compliance. These reports of calcium antagonists also fail to take account of the heterogeneity of these agents, which differ in structure, in onset, duration, and mechanism of action, and in the extent to which they produce neurohormonal activation. The balance between vascular and myocardial effects on heart rate is a prime determinant of myocardial oxygen consumption as well as outcome. Different calcium antagonists, therefore, should not be considered together in the same meta-analysis. It is hoped that the results of the controlled trials, now in progress, will clearly resolve the contradictory results of the case-controlled studies.
PROSPECTIVE, CONTROLLED STUDIES OF CALCIUM ANTAGONISTS
The nisoldipine therapy study: Doppler Flow and
Echocardiography in Functional Cardiac Insufficiency Assessment of Nisoldipine Therapy (DEFIANT II) is a randomized, multicenter, double-blind, and placebocontrolled study of slow-release nisoldipine, a secondgeneration dihydropyridine calcium antagonist. The primary and secondary outcome variables were, respectively, exercise tolerance and echo- and Dopplerderived indices of left ventricular function. The patients in this study were considered at relatively high risk for adverse outcome due to their recent myocardial infarction and left ventricular dysfunction (mean ejection fraction 38%). In this population, 71% of the patients had coexistent hypertension and 51% had anterior myocardial infarctions. The treatment was initiated 7–10 days after the index myocardial infarction. At 6 months follow-up, time to onset of ischemic type ST-segment depression during exercise and several indices of diastolic left ventricular function were significantly improved (p 5 0.03 and p 5 0.005, respectively) in the nisoldipine group. More importantly, after this relatively short period of time, con22H THE AMERICAN JOURNAL OF CARDIOLOGYT
TABLE I Systolic Hypertension in Europe (SYST-EUR) Trial Nonfatal Events (%)
P
A
Risk Reduction
p Value
Stroke Any cardiac event CAD MI Angina CABG/PTCA Cancer
10.0 12.6 7.6 5.5 23.9 10.2 14.7
5.7 8.5 4.9 4.4 18.1 6.9 12.4
244 233 233 220 224 232 215
0.007 0.03 0.05 NS 0.04 0.06 NS
A 5 active; CAD 5 coronary artery disease; CABG 5 coronary artery bypass grafting; MI 5 myocardial infarction; P 5 placebo; PTCA 5 percutaneous transluminal coronary angioplasty.
TABLE II Systolic Hypertension in Europe (SYST-EUR) Trial Fatal Events (%)
P
A
Risk Reduction
p Value
Total deaths CV deaths Stroke CAD MI SD Cancer deaths
24 13.5 3.7 9.1 2.6 4.7 4.4
20 9.8 2.7 6.7 1.2 4.2 3.0
214 227 227 227 256 212 231
NS 0.07 NS NS 0.08 NS NS
A 5 active; CAD 5 coronary artery disease; CV 5 cardiovascular; MI 5 myocardial infarction; P 5 placebo; SD 5 sudden death.
TABLE III Verapamil Hypertension Atherosclerosis Study (VHAS)—Results of Ultrasonography Cardiovascular Events
Cardiovascular events Deaths Progression rate
Chlorthalidone
Verapamil
p Value
35/254 4/254 10.023
19/244 2/244 20.075
p ,0.01
Of 1,414 hypertensive patients, 498 had carotid ultrasound at 3, 12, 24, and 48 months.
vincing trends were observed toward fewer deaths (p ,0.07) and fewer total adverse ischemic heart disease outcomes, such as reinfarction, heart failure, angina (unstable, rest, and effort), and the need for coronary bypass surgery (all p ,0.09).9 The systolic hypertension trial: The Systolic Hypertension in Europe (SYST-EUR) trial10 of nitrendipine, another second-generation long-acting dihydropyridine calcium antagonist, randomized almost 5,000 elderly (60 years) patients (mean age 70 years) with isolated systolic hypertension to either placebo or nitrendipine, with enalapril and hydrochlorothiazide added if needed to control systolic blood pressure. About 30% of the patients had “cardiovascular complications” at entry and about half of these had signs or symptoms suggesting coronary artery disease or cerebrovascular disease. Interestingly, two-thirds of the sample were female. After a median follow-up of 2 years, in the calcium
VOL. 82 (3A)
AUGUST 6, 1998
antagonist group, there was a striking reduction in stroke (42%, p 5 0.003), all cardiovascular events (31%, p ,0.001), all cardiac events (26%, p 5 0.03), angina (24%, p 5 0.04), and trends toward reduction in the incidence of fatal myocardial infarction (56%, p 5 0.08), all myocardial infarction (30%), the incidence of cancer (31%), and bleeding (10%) (Table I). There was a nonstatistically significant reduction in total deaths (14%) and a trend toward reductions in all cardiovascular deaths (27%; p 5 0.07, Table II). The verapamil study: In the Verapamil Hypertension Atherosclerosis Study (VHAS),11 1,414 patients with hypertension were randomized to either sustained-release verapamil or chlorthalidone for 2 years. Captopril was added for those whose blood pressure was not controlled. There were a total of 42 cardiovascular events in the verapamil-treated patients and 41 (p 5 NS) in the chlorthalidone-treated patients. Results from a randomly selected cohort of 498 patients have been reported (Table III).12 This cohort underwent ultrasound studies at 3, 12, 24, and 48 months to measure intimal media thickness of the carotid arteries as an estimate of atherosclerosis. There was a significantly lower frequency of cardiovascular events (p ,0.01) and a trend toward a decreased death rate in the cohort of patients randomized to the calcium antagonist. Progression of atherosclerosis was slower also in this group, as documented by the slope of the change in intimal media thickness over time, normalized for the baseline thickness. These prospective, controlled data raise questions about the traditional approach to the treatment of hypertension, i.e., the first-line use of b blockers or diuretics, with calcium antagonists and angiotensinconverting enzyme (ACE) inhibitors reserved for second-line treatment. The modern approach is instead to
treat hypertension and coronary disease as diseases, respectively, of the systemic and coronary blood vessels, and to target treatment to restore normal function and structure to those vessels. At present, calcium antagonists and ACE inhibitors appear to be the agents with the most beneficial effects on vascular biology. Although the above results are of interest, they do not specifically address the question of what is optimal treatment for the patient with both coronary artery disease and hypertension. We must await the results of ongoing trials in patients with coronary artery disease and hypertension for the definitive answer to this important clinical question.
INTERNATIONAL VERAPAMIL AND TRANDOLAPRIL STUDY These considerations provide the background to the International Verapamil and Trandolapril Study (INVEST), being conducted at the University of Florida. INVEST recruits only hypertensive patients with documented coronary artery disease. INVEST is based on the hypothesis that, in patients with hypertension and coexisting coronary artery disease, adverse outcomes—i.e., all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke— are at least similar whether patients receive treatment with verapamil and verapamil-based additional treatments, if needed, or with b blockers and diuretics. As a first step, patients are randomized to either a calcium-antagonist strategy (e.g., verapamil slow-release, 240 mg once-daily), or to a non– calcium-anatagonist strategy (atenolol, 50 mg once-daily). If adequate blood pressure control is not achieved, those in the non– calcium-anatagonist strategy are given hydrochlorothiazide in addition, with the doses of both agents increased as necessary. If adequate blood pres-
FIGURE 1. International Verapamil and Trandolapril Study (INVEST): study design. A SYMPOSIUM: PATHOGENESIS OF CAD
23H
sure control is still not achieved, the ACE inhibitor trandolapril can be added as a further step. Those patients in the calcium antagonist strategy who need additional medication for blood pressure control will receive trandolapril. The verapamil slow-release dose can then be increased, if needed, to 180 mg twice daily (total daily dose, 360 mg), the trandolapril dose to 4 mg, and hydrochlorothiazide added if blood pressure control is still inadequate (Figure 1). It is anticipated that this stepped approach will achieve adequate control in .90% of patients. INVEST covers 1,200 sites worldwide. The prepilot and pilot studies are now completed and the full study phase is recruiting 27,000 patients who will be treated for at least 2 years.
USE OF THE INTERNET A unique feature of INVEST is that each investigator receives by mail a personal computer (PC), which is ready loaded with all the software for the required documentation, instructions for data entry, and which has direct-dial access to the Internet. All data are entered directly when captured and handled electronically. Data entry and transmission, therefore, are relatively rapid—about 15 minutes per patient. A direct link to a mail-order drug delivery company ensures that the patients’ drugs are mailed for receipt within 2–3 days. The use of the Internet allows not only the rapid collection of data but also an immediate response to requests for reports. Findings, therefore, will be available as soon as the study ends, in the year 2000.
OTHER CALCIUM ANTAGONIST TRIALS A number of other randomized trials of the use of calcium antagonists in hypertension are in progress. Many of them also include patients with coronary disease. However, none—with the exception of the Comparative Efficacy and Safety of Nisoldipine and Amlodipine in Hypertensive Subjects with Ischemic Heart Disease (CESNA II)—focuses specifically on
24H THE AMERICAN JOURNAL OF CARDIOLOGYT
coronary artery disease. CESNA II is a double-blind, multicenter, randomized, parallel group dose titration trial to assess whether once-daily nisoldipine and once-daily amlodipine are equivalent with regard to antihypertensive efficacy in the treatment of patients with mild-to-moderate hypertension and concomitant heart disease. These trials are expected to provide the necessary randomized, controlled data to determine whether or not calcium antagonists are beneficial in the treatment of patients with hypertension and, in particular, those with coexisting coronary artery disease.
1. Pepine CJ, Abrams J, Marks RG, Morris JJ, Scheidt SS, Handberg E, for the TIDES Investigators. Characteristics of a contemporary population with angina pectoris. Am J Cardiol 1994;74:226 –231. 2. Kannel WB, Dannenberg AL, Abbott RD. Unrecognized myocardial infarction and hypertension: the Framingham Study. Am Heart J 1985;109:581–585. 3. Opie L. Review of trials in the treatment of coronary artery disease: theoretical expectations versus lack of practical success— how can we explain the differences? Am J Cardiol 1998;82:15H–20H. 4. Psaty BM, Heckbert SR, Koepsell TD, Siscovick DS, Raghunathan TE, Weiss NS, Rosendaal FR, Lemaitre RN, Smith NL, Wahl PW, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995;274:620 – 625. 5. Jick H, Derby LE, Gurewich V, Vasilakis C. The risk of myocardial infarction associated with antihypertensive drug treatment in persons with uncomplicated essential hypertension. Pharmacotherapy 1996;16:321–326. 6. Aursnes I, Litleskare I, Froyland H, Abdelnoor M. Association between various drugs used for hypertension and risk of acute myocardial infarction. Blood Pressure 1995;4:157-163. 7. Leader SG, Mallick R, Briggs NC. Myocardial infarction in newly diagnosed hypertensive Medicaid patients free of coronary heart disease and treated with calcium channel blockers. Am J Med 1997;102:150-157. 8. Alderman MH, Madhavan S. Ooi WL, Cohen H., Sealey JE, Laragh JH. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 1991;324:1098-1104. 9. The DEFIANT-II Research Group. Doppler flow and echocardiography in functional cardiac insufficiency: assessment of nisoldipine therapy. Results of the DEFIANT-II Study. Eur Heart J 1997;18:31– 40. 10. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenho¨ger WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O’Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A., for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350:757–764. 11. Rosei EA, Dal Palu C, Leonetti G, Magnani B, Pessina A, Zanchetti A. Clinical results of the Verapamil in Hypertension and Atherosclerosis Study. J Hypertens 1997;15:1337–1344. 12. Zanchetti A. J Hypertension 1997; 15 (suppl 4A):S91.
VOL. 82 (3A)
AUGUST 6, 1998
MD
In the United States alone, it is estimated that 60 million people have hypertension, the estimate varying according to whether hypertension is defined as a blood pressure of >140/90 mm Hg or, as has emerged from the Sixth Joint National Commission on Hypertension (JNC VI) consensus conference, of >130/90 mm Hg. Coronary artery disease frequently accompanies hypertension. In our studies of >5,000 patients with coronary artery disease, half had hypertension. The reasons are numerous. Hypertension is a major risk factor for CAD. The incidence of both conditions increases with age, so that the majority of individuals >65 years of age with
coronary artery disease probably also have hypertension. Some authorities predict that, due to the increasing size of the elderly population, there will be a doubling in the prevalence of both coronary artery disease and hypertension in the next century. This is of vital concern to all clinicians. This article reviews some of the prevalence and population trends in coronary artery disease and hypertension, and some of the pathogenic mechanisms involved, as well the results of some current outcome trials. Q1998 by Excerpta Medica, Inc. Am J Cardiol 1998;82:21H–24H
ypertension is a risk factor for angina. In our contemporary cohort study of 5,000 patients with H angina, half also had hypertension, and the frequency
THE IDEAL ANTI-ISCHEMIC/ ANTIHYPERTENSIVE AGENT
of both conditions increased with age.1 The Framingham study2 showed that the risk of all coronary artery disease complications is approximately doubled in the presence of hypertension. Hypertension is a major risk factor both for symptomatic and for “silent” or unrecognized myocardial infarction, for example. In the elderly, silent myocardial infarctions comprise a considerable proportion of the total; in the Framingham study, half or more of all myocardial infarctions in individuals aged .65 years were silent. These silent myocardial infarctions are clinically important because they carry the same long-term prognosis as recognized myocardial infarctions. Silent or unrecognized ischemic heart disease in hypertensive patients is particularly relevant to concerns about calcium antagonists,3 which are further discussed below. The risk of sudden death, heart failure, and all-cause mortality are also increased in hypertensive individuals.
PATHOPHYSIOLOGY Current evidence suggests that hypertension, via increased oxidant stress, damages endothelium. This evokes a number of responses that disrupt the balance between processes such as constriction/dilation, proliferation/antiproliferation, thrombosis/antithrombosis, and fibrinolysis/antifibrinolysis. These consequences of endothelial dysfunction may lead to transient ischemia (through hypoperfusion) or ischemiarelated adverse outcomes (coronary thrombosis, sudden death). From the Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida. Address for reprints: Carl J. Pepine, MD, Division of Cardiology, University of Florida College of Medicine, 1600 SW Archer Road, Box 100277, Gainesville, Florida 32610. ©1998 by Excerpta Medica, Inc. All rights reserved.
Based on these epidemiologic and pathophysiologic considerations, and on our understanding of vascular biology, the ideal anti-ischemic/antihypertensive agent should prevent ischemia-related outcomes (e.g., death and myocardial infarction). It should also: (1) restore vascular function and structure; (2) halt deterioration of endothelial function; (3) inhibit vasoconstriction, not only in the coronary circulation, but also in the renal and cerebral circulations; (4) improve left ventricular diastolic function and reverse or prevent left ventricular hypertrophy, if present; (5) have antithrombotic and profibrinolytic activity; (6) have antioxidant activity; (7) be well tolerated as a once-daily formulation; and (8) be safe in combination with other agents, because a single agent is often inadequate to manage patients with both ischemic heart disease and hypertension.
RETROSPECTIVE, CASE-CONTROLLED STUDIES OF CALCIUM ANTAGONISTS Calcium antagonists initially appeared as an attractive option for management of patients with ischemic heart disease and hypertension, and were frequently used for .20 years. Yet, as discussed elsewhere in this symposium,3 data on clinical outcome, specifically myocardial infarction and death, were lacking. The first case-controlled data appeared in 19954 and suggested that, in patients with presumably uncomplicated hypertension, treatment with various short-acting, first-generation calcium antagonists—as opposed to b blockers and diuretics—was associated with a 60% excess risk for adverse outcome. There were only 56 cases and 170 controls, and the confidence intervals were wide (e.g., 4 –239%). Yet another study,5 using the same methodology, reported that these same calcium antagonists, plus amlodipine, were associated with a decreased risk of adverse outcome of approximately 30% when compared with b blockers and diuretics. In this report, the diagnosis of acute myo0002-9149/98/$19.00 PII S0002-9149(98)00487-1
21H
cardial infarction was documented by in-hospital records; the data suggested a 10% reduction for acute myocardial infarction, but with wide confidence intervals. Three other reports (Aursnes et al,6 Leader et al,7 and Alderman et al8) also suggested a decrease in risk for myocardial infarction of approximately 37% (ranging from 24 –51%). Furthermore, the earlier study4 suggested approximately the same excess risks for myocardial infarction (;60%) in patients with and without pre-existing cardiovascular disease. Clearly these results are inconsistent with our current understanding of the mechanisms of action of these agents as well as the pathogenesis and outcomes of the diseases they are used to treat. These conflicting findings may be attributable to a number of methodologic shortcomings in these retrospective, case-controlled studies. In particular, there was no assessment of the control or the severity of the hypertension, or of the presence or severity of associated coronary artery disease, especially when in the form of an unrecognized myocardial infarction or ischemia. In addition, there was no assessment of patient compliance. These reports of calcium antagonists also fail to take account of the heterogeneity of these agents, which differ in structure, in onset, duration, and mechanism of action, and in the extent to which they produce neurohormonal activation. The balance between vascular and myocardial effects on heart rate is a prime determinant of myocardial oxygen consumption as well as outcome. Different calcium antagonists, therefore, should not be considered together in the same meta-analysis. It is hoped that the results of the controlled trials, now in progress, will clearly resolve the contradictory results of the case-controlled studies.
PROSPECTIVE, CONTROLLED STUDIES OF CALCIUM ANTAGONISTS
The nisoldipine therapy study: Doppler Flow and
Echocardiography in Functional Cardiac Insufficiency Assessment of Nisoldipine Therapy (DEFIANT II) is a randomized, multicenter, double-blind, and placebocontrolled study of slow-release nisoldipine, a secondgeneration dihydropyridine calcium antagonist. The primary and secondary outcome variables were, respectively, exercise tolerance and echo- and Dopplerderived indices of left ventricular function. The patients in this study were considered at relatively high risk for adverse outcome due to their recent myocardial infarction and left ventricular dysfunction (mean ejection fraction 38%). In this population, 71% of the patients had coexistent hypertension and 51% had anterior myocardial infarctions. The treatment was initiated 7–10 days after the index myocardial infarction. At 6 months follow-up, time to onset of ischemic type ST-segment depression during exercise and several indices of diastolic left ventricular function were significantly improved (p 5 0.03 and p 5 0.005, respectively) in the nisoldipine group. More importantly, after this relatively short period of time, con22H THE AMERICAN JOURNAL OF CARDIOLOGYT
TABLE I Systolic Hypertension in Europe (SYST-EUR) Trial Nonfatal Events (%)
P
A
Risk Reduction
p Value
Stroke Any cardiac event CAD MI Angina CABG/PTCA Cancer
10.0 12.6 7.6 5.5 23.9 10.2 14.7
5.7 8.5 4.9 4.4 18.1 6.9 12.4
244 233 233 220 224 232 215
0.007 0.03 0.05 NS 0.04 0.06 NS
A 5 active; CAD 5 coronary artery disease; CABG 5 coronary artery bypass grafting; MI 5 myocardial infarction; P 5 placebo; PTCA 5 percutaneous transluminal coronary angioplasty.
TABLE II Systolic Hypertension in Europe (SYST-EUR) Trial Fatal Events (%)
P
A
Risk Reduction
p Value
Total deaths CV deaths Stroke CAD MI SD Cancer deaths
24 13.5 3.7 9.1 2.6 4.7 4.4
20 9.8 2.7 6.7 1.2 4.2 3.0
214 227 227 227 256 212 231
NS 0.07 NS NS 0.08 NS NS
A 5 active; CAD 5 coronary artery disease; CV 5 cardiovascular; MI 5 myocardial infarction; P 5 placebo; SD 5 sudden death.
TABLE III Verapamil Hypertension Atherosclerosis Study (VHAS)—Results of Ultrasonography Cardiovascular Events
Cardiovascular events Deaths Progression rate
Chlorthalidone
Verapamil
p Value
35/254 4/254 10.023
19/244 2/244 20.075
p ,0.01
Of 1,414 hypertensive patients, 498 had carotid ultrasound at 3, 12, 24, and 48 months.
vincing trends were observed toward fewer deaths (p ,0.07) and fewer total adverse ischemic heart disease outcomes, such as reinfarction, heart failure, angina (unstable, rest, and effort), and the need for coronary bypass surgery (all p ,0.09).9 The systolic hypertension trial: The Systolic Hypertension in Europe (SYST-EUR) trial10 of nitrendipine, another second-generation long-acting dihydropyridine calcium antagonist, randomized almost 5,000 elderly (60 years) patients (mean age 70 years) with isolated systolic hypertension to either placebo or nitrendipine, with enalapril and hydrochlorothiazide added if needed to control systolic blood pressure. About 30% of the patients had “cardiovascular complications” at entry and about half of these had signs or symptoms suggesting coronary artery disease or cerebrovascular disease. Interestingly, two-thirds of the sample were female. After a median follow-up of 2 years, in the calcium
VOL. 82 (3A)
AUGUST 6, 1998
antagonist group, there was a striking reduction in stroke (42%, p 5 0.003), all cardiovascular events (31%, p ,0.001), all cardiac events (26%, p 5 0.03), angina (24%, p 5 0.04), and trends toward reduction in the incidence of fatal myocardial infarction (56%, p 5 0.08), all myocardial infarction (30%), the incidence of cancer (31%), and bleeding (10%) (Table I). There was a nonstatistically significant reduction in total deaths (14%) and a trend toward reductions in all cardiovascular deaths (27%; p 5 0.07, Table II). The verapamil study: In the Verapamil Hypertension Atherosclerosis Study (VHAS),11 1,414 patients with hypertension were randomized to either sustained-release verapamil or chlorthalidone for 2 years. Captopril was added for those whose blood pressure was not controlled. There were a total of 42 cardiovascular events in the verapamil-treated patients and 41 (p 5 NS) in the chlorthalidone-treated patients. Results from a randomly selected cohort of 498 patients have been reported (Table III).12 This cohort underwent ultrasound studies at 3, 12, 24, and 48 months to measure intimal media thickness of the carotid arteries as an estimate of atherosclerosis. There was a significantly lower frequency of cardiovascular events (p ,0.01) and a trend toward a decreased death rate in the cohort of patients randomized to the calcium antagonist. Progression of atherosclerosis was slower also in this group, as documented by the slope of the change in intimal media thickness over time, normalized for the baseline thickness. These prospective, controlled data raise questions about the traditional approach to the treatment of hypertension, i.e., the first-line use of b blockers or diuretics, with calcium antagonists and angiotensinconverting enzyme (ACE) inhibitors reserved for second-line treatment. The modern approach is instead to
treat hypertension and coronary disease as diseases, respectively, of the systemic and coronary blood vessels, and to target treatment to restore normal function and structure to those vessels. At present, calcium antagonists and ACE inhibitors appear to be the agents with the most beneficial effects on vascular biology. Although the above results are of interest, they do not specifically address the question of what is optimal treatment for the patient with both coronary artery disease and hypertension. We must await the results of ongoing trials in patients with coronary artery disease and hypertension for the definitive answer to this important clinical question.
INTERNATIONAL VERAPAMIL AND TRANDOLAPRIL STUDY These considerations provide the background to the International Verapamil and Trandolapril Study (INVEST), being conducted at the University of Florida. INVEST recruits only hypertensive patients with documented coronary artery disease. INVEST is based on the hypothesis that, in patients with hypertension and coexisting coronary artery disease, adverse outcomes—i.e., all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke— are at least similar whether patients receive treatment with verapamil and verapamil-based additional treatments, if needed, or with b blockers and diuretics. As a first step, patients are randomized to either a calcium-antagonist strategy (e.g., verapamil slow-release, 240 mg once-daily), or to a non– calcium-anatagonist strategy (atenolol, 50 mg once-daily). If adequate blood pressure control is not achieved, those in the non– calcium-anatagonist strategy are given hydrochlorothiazide in addition, with the doses of both agents increased as necessary. If adequate blood pres-
FIGURE 1. International Verapamil and Trandolapril Study (INVEST): study design. A SYMPOSIUM: PATHOGENESIS OF CAD
23H
sure control is still not achieved, the ACE inhibitor trandolapril can be added as a further step. Those patients in the calcium antagonist strategy who need additional medication for blood pressure control will receive trandolapril. The verapamil slow-release dose can then be increased, if needed, to 180 mg twice daily (total daily dose, 360 mg), the trandolapril dose to 4 mg, and hydrochlorothiazide added if blood pressure control is still inadequate (Figure 1). It is anticipated that this stepped approach will achieve adequate control in .90% of patients. INVEST covers 1,200 sites worldwide. The prepilot and pilot studies are now completed and the full study phase is recruiting 27,000 patients who will be treated for at least 2 years.
USE OF THE INTERNET A unique feature of INVEST is that each investigator receives by mail a personal computer (PC), which is ready loaded with all the software for the required documentation, instructions for data entry, and which has direct-dial access to the Internet. All data are entered directly when captured and handled electronically. Data entry and transmission, therefore, are relatively rapid—about 15 minutes per patient. A direct link to a mail-order drug delivery company ensures that the patients’ drugs are mailed for receipt within 2–3 days. The use of the Internet allows not only the rapid collection of data but also an immediate response to requests for reports. Findings, therefore, will be available as soon as the study ends, in the year 2000.
OTHER CALCIUM ANTAGONIST TRIALS A number of other randomized trials of the use of calcium antagonists in hypertension are in progress. Many of them also include patients with coronary disease. However, none—with the exception of the Comparative Efficacy and Safety of Nisoldipine and Amlodipine in Hypertensive Subjects with Ischemic Heart Disease (CESNA II)—focuses specifically on
24H THE AMERICAN JOURNAL OF CARDIOLOGYT
coronary artery disease. CESNA II is a double-blind, multicenter, randomized, parallel group dose titration trial to assess whether once-daily nisoldipine and once-daily amlodipine are equivalent with regard to antihypertensive efficacy in the treatment of patients with mild-to-moderate hypertension and concomitant heart disease. These trials are expected to provide the necessary randomized, controlled data to determine whether or not calcium antagonists are beneficial in the treatment of patients with hypertension and, in particular, those with coexisting coronary artery disease.
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