Evolving Treatment Options for Prevention of Cardiovascular Events in High‐Risk Hypertensive Patients

Abstract

The identification and treatment of high‐risk patients for cardiovascular disease reduces the risk of morbidity and mortality. Significant risk factors for cardiovascular events in hypertensive patients over and above dyslipidemia, smoking, and obesity include coronary heart disease, peripheral arterial disease, cerebrovascular/carotid artery disease, and diabetes. Treatment options for the reduction of cardiovascular events in hypertensive patients include diuretics, β‐blockers, α‐blockers, calcium channel blockers, angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone antagonists. All of these agents, in various combinations, have been found to reduce the risk of cardiovascular events, even in high‐risk patients. The use of ACE inhibitors or ARBs (usually in combination with a diuretic) has proven especially effective in reducing cardiovascular events in diabetes and, although both classes of drugs target the renin‐angiotensin‐aldosterone system, each has a different mechanism of action. Some investigators believe that combination therapy with an ACE inhibitor and ARB, usually given with other medications, may be more effective than either agent alone with other drugs. The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) is evaluating the cardioprotective effect of an ACE inhibitor (ramipril) plus an ARB (telmisartan) in high‐risk patients.

Cardiovascular disease is the leading cause of death in the United States. ¹ Hypertension is correlated with a significant risk for stroke, coronary heart disease (CHD), heart failure (HF), myocardial infarction (MI), atrial fibrillation, end‐stage renal disease, peripheral vascular disease, and left ventricular hypertrophy. ² , ³ Patients with diabetes, coronary artery disease (CAD), peripheral arterial disease, or a previous stroke or transient ischemic attack are at the greatest risk for cardiovascular (CV) events. ¹ , ³ , ⁴ , ⁵

Identifying and treating risk factors in patients at high risk for CV events can significantly reduce the risk of CV morbidity and mortality. Blood pressure (BP) control with antihypertensive therapy has been shown to reduce risk of stroke, MI, and HF by 20% to 50%. ⁶ Numerous antihypertensive agents have been successfully used to control hypertension; the treatment of high‐risk patients requires comprehensive risk‐factor management and preventive interventions. ⁷ Although many experts believe that the levels of BP are the major determinants of benefit, the use of angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) may have some CV benefits in addition to BP control. ⁸ , ⁹ , ¹⁰ , ¹¹

RISK FACTORS FOR CV EVENTS

Many CV risk factors have been identified, including hypertension, hyperlipidemia, obesity, diabetes, smoking, age, male sex, and family history. ¹² The risk of a CV event increases dramatically in patients with a history of CV disease. Many (15% to 44%) patients with a prior stroke will develop clinical manifestations of coronary disease or cardiac failure. ¹ Between 20% and 46% of patients with peripheral arterial disease will develop stroke, cardiac failure, or CAD. ¹ In patients with diabetes, heart disease and stroke account for 65% of all deaths; diabetes has been considered by some but not all investigators to be a CHD risk equivalent. ¹³ , ¹⁴

Many patients have comorbid conditions of hypertension, diabetes, and dyslipidemia. ¹ The risk of CV events increases with the severity and number of risk factors (Figure 1). ⁷ , ¹² , ¹⁵ The Multiple Risk Factor Intervention Trial (MRFIT) ¹⁵ demonstrated that the number of CV risk factors significantly increases the risk of CV mortality from 24.7 per 10,000 person‐years in nondiabetic patients to 77.8 per 10,000 person‐years in high‐risk patients with diabetes who have up to 3 risk factors. Because of the many factors influencing a patient's risk for CV events, patients at high risk for a CV event require early and aggressive intervention.

Figure 1.

Ten‐year risk for coronary heart disease (CHD) by systolic blood pressure (SBP) and the presence of other cardiovascular risk factors. The risk of cardiovascular disease increases with increasing blood pressure and the presence of additional risk factors. HDL indicates high‐density lipoprotein; LVH, left ventricular hypertrophy. Adapted with permission from the Seventh Report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure. ⁷

USE OF DIURETICS AND β‐BLOCKERS FOR THE PREVENTION OF CV EVENTS

Diuretics

Although a number of therapeutic agents are currently available, the appropriate selection of antihypertensive drug therapy depends on a patient's underlying risk for CV events. Diuretics have been recommended as the preferred first‐step antihypertensive therapy for patients with uncomplicated hypertension. ⁷ The blinded, controlled Antihypertensive and Lipid‐lowering Treatment to Prevent Heart Attack Trial (ALLHAT) ¹⁶ demonstrated that diuretics were superior to calcium channel blockers (CCBs) or ACE inhibitors in preventing CV disease and improving survival in patients with hypertension and at least 1 other risk factor for CHD. Patients were randomized in this blinded study to receive chlorthalidone, amlodipine, or lisinopril. In nonblack patients, BP lowering was similar among the 3 treatment groups. Patients receiving amlodipine had a 38% higher risk of HF, whereas patients receiving lisinopril had a 15% higher risk for stroke and a 10% higher risk of combined CV disease compared with patients receiving a chlorthalidone‐based treatment regimen. In black patients, BP lowering was greater with the diuretic than with the ACE inhibitor, which may have accounted for some of the differences in stroke outcome.

In a meta‐analysis of 42 clinical trials, low‐dose diuretics were reputed to be the most effective first‐step treatment for preventing CV disease morbidity and mortality. ¹⁷ Patients receiving diuretics had a lower risk of congestive HF, stroke, and CV disease events when compared with those receiving ACE inhibitors and a lower risk of congestive HF and CV events than patients receiving CCBs. Thus, these agents have been established as effective antihypertensive agents.

β‐Blockers

β‐Blockers reduce CV risk compared with placebo in patients with uncomplicated hypertension but may not be as effective in reducing risk when compared with other antihypertensive agents. Although the primary outcome of fatal and nonfatal CHD events did not differ, a prospective, multicenter, randomized trial comparing an amlodipine‐based regimen with an atenolol‐based regimen in 19,257 patients was terminated early due to a lower rate of nonfatal MI, fatal CAD, total coronary events and CV procedures, and stroke in patients taking amlodipine. ¹⁸ A meta‐analysis of 13 randomized controlled trials including 105,951 patients with primary hypertension reported that treatment with a β‐blocker, predominantly atenolol, reduced the relative risk of stroke by 19% compared with placebo, but the relative risk of stroke was 16% higher for patients receiving β‐blockers compared with those receiving other antihypertensive agents, with no difference in the reduction in risk of MI or mortality. ¹⁹ β‐Blockers may not reduce the risk for CV events to the degree of other agents because of decreased insulin sensitivity or a dose‐dependent increase in triglycerides in patients with hypertension. There are differences among β‐blocking drugs. ²⁰ , ²¹

β‐Blockers have different effects on CV events, including stroke, in young and elderly patients. A meta‐analysis of 21 hypertension trials enrolling 145,811 patients demonstrated that β‐blockers reduce CV death, MI, or stroke compared with placebo in younger but not in elderly patients. ²² In a systematic review of 10 trials enrolling 16,164 elderly patients, β‐blockers reduced the risk of cerebrovascular events, but not CHD, CV mortality, or all‐cause mortality and were inferior to diuretics for all end points, including the prevention of stroke. ²³ Thus, β‐blockers without α‐blocking or vasodilating effects may not be preferred medication for hypertension management, especially in the elderly.

Recently, the National Institute for Health and Clinical Excellence, which advises on treatment guidelines for the National Health Service in England and Wales, removed β‐blockers from its recommendations for first‐step treatment of hypertension. ²⁴ The guidelines from the British Hypertensive Society also recommend against β‐blockers in patients at high risk for diabetes. ³ These agents are, however, still recommended in patients with angina, post‐MI, and various arrhythmias.

RENIN‐ANGIOTENSIN‐ALDOSTERONE SYSTEM INHIBITION FOR THE PREVENTION OF CV EVENTS

Blockade of the renin‐angiotensin‐aldosterone system (RAAS) reduces BP and, when used with other antihypertensive drugs (especially diuretics) reduces CV events and has decreased the risk of diabetes in some studies. ²⁵ Cardioprotective effects of agents that inhibit the RAAS may not be totally dependent on control of hypertension alone. There is some experimental evidence to suggest this. Angiotensin II‐mediated generation of reactive oxygen species, endothelial dysfunction, and inflammation contribute to risk for CV events and diabetic complications. ⁸ , ¹⁰ , ²⁶ In an in vivo rat model of streptozotocin‐induced diabetes, the ACE inhibitor lisinopril attenuated production of reactive oxygen species, reduced oxidative stress, and prevented cardiomyocyte hypertrophy. ⁸ In a rat model of MI, RAAS inhibition by the ARB losartan improved cardiac function and myocardial antioxidant reserve, reduced cardiac remodeling, and decreased oxidative stress. ⁹

In a small study of 10 healthy patients, RAAS inhibition by either an ACE inhibitor, perindopril, or losartan prevented free fatty acid‐induced endothelial dysfunction, measured by forearm vasodilation, which is characteristic of the high plasma free fatty acid levels and reduced vasodilation in patients with type 2 diabetes and the metabolic syndrome, and is predictive of CV events. ¹¹ RAAS blockade may also reduce angiotensin II‐mediated inflammation by reducing induction of nuclear factor‐κB, expression of vascular cell adhesion molecules, and release of inflammatory cytokines, such as interleukin 6. ¹⁰

Clinical Trials

The clinical benefit of RAAS inhibition has been demonstrated in several clinical trials. The Heart Outcomes Prevention Evaluation (HOPE) ²⁷ showed that during the mean 4.5‐year follow‐up period, treatment with ramipril plus other antihypertensive medications reduced the risk of CV events, CV death, and the development of diabetes in high‐risk patients aged 55 years and older with preserved ventricular function and vascular disease to a greater degree than a regimen that did not include an ACE inhibitor. The incidence of MI, stroke, or death from CV causes was 14% in patients on the ACE inhibitor treatment compared with 17.8% in patients on therapy other than an ACE inhibitor (P<.001). In HOPE‐The Ongoing Outcomes (HOPE‐TOO), ²⁸ which provided an additional 2.6 years of follow‐up, patients in the ACE inhibitor group had an additional 19% relative risk reduction for MI, a 16% lower relative risk of revascularization, and a 34% lower relative risk of developing diabetes.

In the Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) trial, ²⁹ , ³⁰ however, rosiglitazone, but not ramipril, prevented the development of diabetes or death in patients with impaired glucose tolerance or impaired fasting glucose but without evidence of diabetes or CV disease. In the Anglo‐Scandinavian Cardiac Outcomes Trial (ASCOT)‐Blood Pressure‐Lowering Arm, which evaluated the frequency of nonfatal MI and fatal CHD in 19,257 patients with hypertension and at least 3 additional CV risk factors, an amlodipine‐based regimen that included an ACE inhibitor did not prevent CHD events to a greater extent than an atenolol‐based regimen that included a diuretic, but reduced overall CV events to a greater degree (a rate per 1000 patient‐years of 27.4 and 32.8, respectively), with a hazard ratio of 0.84 (95% confidence interval, 0.78–0.90; P<.0001). ¹⁸ Treatment with the CCB‐ and ACE inhibitor‐containing regimen reduced the development of diabetes compared with the atenolol‐based regimen, with a rate per 1000 patient‐years of 11.0 and 15.9, respectively (hazard ratio, 0.70; 95% confidence interval, 0.63–0.78; P<.0001).

The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study ³¹ demonstrated that ARB‐based therapy with losartan was superior to β‐blocker‐based therapy with atenolol in preventing CV morbidity and mortality in >9100 patients with hypertension and left ventricular hypertrophy. Treatment with the ARB resulted in a 14.5% relative risk reduction in the composite end point of CV mortality, stroke, and MI. Most of the benefit was, however, related to a reduction in stroke. In the Valsartan Antihypertensive Long‐Term Use Evaluation (VALUE) trial, ³² comparison of an ARB (valsartan)‐ and a calcium antagonist (amlodipine)‐based regimen in >15,000 high‐risk patients with hypertension revealed no differences in the composite end point of morbidity and mortality. In this trial, however, amlodipine reduced BP and the occurrence of MI more than the ARB valsartan. A nonsignificant trend for greater reduction of HF and a 23% reduction of new‐onset diabetes was, however, observed in patients receiving valsartan. This is one of many studies suggesting that lowering BP is the primary mechanism for CV risk reduction. All of these recent trials used either an ACE inhibitor or an ARB in addition to other agents as comparators.

COMBINATION THERAPY WITH AN ACE INHIBITOR AND AN ARB

ACE inhibitors block formation of angiotensin II and degradation of bradykinin, a powerful vasodilator, whereas ARBs directly inhibit the binding of angiotensin II to angiotensin II type 1 receptors peripherally. ³³ ACE inhibitors may also not completely block alternative pathways for the formation of angiotensin II. Angiotensin II levels may return to normal with chronic ACE inhibition. This has been termed ACE escape, suggesting poor long‐term inhibition of the RAAS. ³⁴ ACE inhibitors and ARBs, therefore, may be synergistic because of different mechanisms of action. ³⁴

Some but not all studies have reported that combination therapy with an ACE inhibitor and ARB is more effective than monotherapy in lowering BP. ³⁴ , ³⁵ , ³⁶ , ³⁷ Therapy with both of these agents has been shown to reduce proteinuria in patients with type 2 diabetes to a greater degree than monotherapy with either one. ³⁵ , ³⁶ A small study of 20 hypertensive patients with type 2 diabetes and nephropathy reported that the addition of the ARB candesartan to ACE inhibitor therapy significantly reduced albuminuria by 28% (P<.001) compared with ACE inhibitor monotherapy. ³⁴ , ³⁵

In another study of 108 patients with progressive chronic renal disease, the combination of an ARB and an ACE inhibitor reduced diastolic BP by 12.6±8.7 mm Hg compared with 2.0±14.0 mm Hg in patients receiving the ARB alone (P=.00009). ³⁶ Likewise, systolic BP was reduced by combination therapy with an ACE inhibitor and an ARB (21.6±16.2 mm Hg) compared with the ARB alone (P=.024). The combination of valsartan and benazepril resulted in a 0.82±1.63 reduction in the urinary protein:creatinine ratio from baseline to the end of the study compared with valsartan alone (P=.047).

The Candesartan and Lisinopril Microalbuminuria (CALM) study ³⁷ evaluated the effects of a combination of candesartan and lisinopril on BP and urinary albumin excretion in 197 patients with microalbuminuria, hypertension, and type 2 diabetes. At 24 weeks, the combination reduced diastolic BP 16.3 mm Hg compared with 10.4 mm Hg for candesartan and 10.7 mm Hg for lisinopril alone (P<.001) (Figure 2). ³⁷ Combination therapy reduced the urinary albumin:creatinine ratio by 50% compared with 24% for candesartan and 39% for lisinopril alone (P<.001).

Figure 2.

Mean systolic and diastolic blood pressures in patients with type 2 diabetes, hypertension, and microalbuminuria treated with either candesartan, lisinopril, or their combination. Adapted with permission from Mogensen et al. ³⁷

In the Valsartan in Acute Myocardial Infarction (VALIANT) study, ³⁸ however, where valsartan was as effective as captopril in patients at high risk for CV events after MI, combining valsartan with captopril increased the rate of adverse events without improving survival. Thus, while some results suggest that an ACE inhibitor/ARB combination with a more complete blockade of the RAAS system than either agent alone may prove to be more effective than the use of either agent alone, the issue has not been settled.

The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) ³⁹ is a randomized, double‐blind study in >23,000 high‐risk patients to evaluate the cardioprotective effects of telmisartan, ramipril, or their combination. This study, which will be reported in 2008, may help to answer the question of whether ACE inhibitor plus ARB therapy (plus other medications) is superior to the use of an ACE inhibitor or ARB alone.

CONCLUSIONS

The identification of patients at high risk for CV events is important for reduction of CV mortality and morbidity. This helps to establish BP goals and direct therapy toward the use of specific antihypertensive agents. ⁷

Patients with uncomplicated hypertension without indications for a specific antihypertensive agent should initially be treated with a diuretic for control of BP. ⁷ , ¹⁶ β‐Blockers may not be an appropriate choice as a primary or secondary antihypertensive agent in patients without a specific indication. The use of β‐blockers may worsen glycemic control and may not be as effective as other agents in reducing stroke, particularly in elderly patients. ¹⁹ , ²¹ , ⁴⁰ In trials with high‐risk hypertensive patients, the use of ACE inhibitors or ARBs (usually along with a diuretic) as well as the use of CCBs and diuretics have resulted in favorable CV outcomes. ¹⁸ , ²⁷ , ²⁸ , ³⁰

It is possible, but not proven, that ARBs and ACE inhibitors in combination may be more effective than other antihypertensive agents in reducing risk of CV events in high‐risk patients. ³¹ , ³² These agents may have some beneficial CV effects that are independent of BP control. ¹ , ⁸ , ⁹ , ¹⁰ , ¹¹ Further studies, such as the ONTARGET trial comparing an ACE inhibitor (ramipril) with an ARB (telmisartan) alone or in combination, will help to determine the benefit of these therapies for preventing CV disease in patients at high risk. ³⁹

Ackowledgment and disclosure:

Editorial assistance for the development of this manuscript was provided by Mary Ellen Shepard, PhD, Boehringer Ingelheim Pharmaceuticals, Inc. This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc.