Cardiovascular Disease Continuum Research Articles

The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes

Fifteen years ago, a panel of experts representing the full spectrum of cardiovascular disease (CVD) research and practice assembled at a workshop to examine the state of knowledge about CVD. The leaders of the workshop generated a hypothesis that framed CVD as a chain of events, initiated by a myriad of related and unrelated risk factors and progressing through numerous physiological pathways and processes to the development of end-stage heart disease (Figure 1). 1 They further hypothesized that intervention anywhere along the chain of events leading to CVD could disrupt the pathophysiological process and confer cardioprotection. The workshop participants endorsed this paradigm but also identified the unresolved issues relating to the concept of a CVD continuum. There was limited availability of clinical trial data and pathobiological evidence at that time, and the experts recognized that critical studies at both the mechanistic level and the clinical level were needed to validate the concept of a chain of events leading to end-stage CVD. In the intervening 15 years, new evidence for underlying pathophysiological mechanisms, the development of novel therapeutic agents, and the release of additional landmark clinical trial data have confirmed the concept of a CVD continuum and reinforced the notion that intervention at any point along this chain can modify CVD progression. In addition, the accumulated evidence indicates that the events leading to disease progression overlap and intertwine and do not always occur as a sequence of discrete, tandem incidents. Furthermore, although the original concept focused on risk factors for coronary artery disease (CAD) and its sequelae, the CVD continuum has expanded to include other areas such as cerebrovascular disease, peripheral vascular disease, and renal disease. Since its conception 15 years ago, the CVD continuum has become much in need of an update. Accordingly, this 2-part article will present a critical and comprehensive update of the current evidence for a CVD continuum based on the results of pathophysiological studies and the outcome of a broad range of clinical trials that have been performed in the past 15 years. It is not the intent of the article to include a comprehensive listing of all trials performed as part of the CVD continuum; instead, we have sought to include only those trials that have had the greatest impact. Part I briefly reviews the current understanding of the pathophysiology of CVD and discusses clinical trial data from risk factors for disease through stable CAD. Part II continues the review of clinical trial data beginning with acute coronary syndromes and continuing through extension of the CVD continuum to stroke and renal disease. The article concludes with a discussion of areas in which future research might further clarify our understanding of the CVD continuum.

Pharmacotherapy for Prehypertension — Mission Accomplished?

Prehypertension, defined as the blood-pressure range of 120 to 139 mm Hg systolic or 80 to 89 mm Hg diastolic, is present in about 70 million Americans.1,2 The condition heralds arterial hypertension and thus may be considered a starting point in the cardiovascular disease continuum. Because of its high prevalence and long-term complications, prehypertension has been estimated to decrease the average life expectancy by as much as five years.35 Unfortunately, current preventive strategies, although admirable from both individual and societal perspectives, are weak.In this issue of the Journal, the investigators of the Trial of Preventing Hypertension (TROPHY) . . .

Clinical Evidence for the Cardiovascular Benefits of Angiotensin Receptor Blockers

Targeting the renin-angiotensin-aldosterone system (RAAS), specifically the effector peptide angiotensin II (Ang II), represents a major opportunity for slowing the progression of cardiovascular disease (CVD) and, in turn, reducing the risk of morbidity and mortality. Inhibition of angiotensin-converting enzyme (ACE) and selective blockade of Ang II AT1 receptors are two approaches through which the pathophysiological effects of Ang II can be targeted. Numerous clinical studies have established the benefits of ACE inhibitors (ACE-Is) in lessening the morbidity and mortality burden of CVD. There are, however, tolerability concerns associated with ACE-Is, such as angioedema and dry cough. By blocking Ang II at the AT1 receptor level, Ang II receptor blockers (ARBs) provide a more specific and complete blockade of the deleterious effects of Ang II and tend to have more favourable tolerability. A number of clinical trials have shown that ARBs are not only associated with positive outcomes across the CVD continuum but mat also have a role in the prevention or delay of diabetes (a major cardiovascular risk factor). Ongoing trials are aiming to define the place of such agents in lessening morbidity and mortality from CVD.

Evidence-based medicine in hypertension: what type of evidence?

Although placebo-controlled trials have been a powerful instrument to answer the question whether blood pressure lowering in hypertensive patients were beneficial or not, event-based trials comparing different active treatments have been less successful, and have generated the opinion that blood pressure lowering is the only relevant beneficial mechanism. Several limitations of these event-based trials should be considered, however only a proportion of the patients have received the initial randomized treatment alone, the goal reducing blood pressure level has rarely been achieved and small blood pressure differences have often been underestimated, patients have been randomized to given regimens as if blood pressure of all them should be equally responsive to different agents, and, finally, most trials have only included elderly or complicated hypertensive. The hypothesis is advanced that blood pressure lowering and ancillary properties of antihypertensive agents may play a different role at various stages of the continuum of cardiovascular disease. Only when hypertension-related complications are not too advanced, the different ability of different antihypertensive agents to influence subclinical organ damage progression ("intermediate" endpoints) may be capable of influencing morbidity and mortality over a longer term than that usually explored by event-based trials.

Angiotensin Receptor Blockers versus ACE Inhibitors: Prevention of Death and Myocardial Infarction in High-Risk Populations

To determine, through a review of the medical literature, whether there is adequate evidence to support the use of angiotensin receptor blockers (ARBs) in place of angiotensin-converting enzyme (ACE) inhibitors in high-risk populations, focusing on the prevention of death and myocardial infarction (MI). Original investigations, reviews, and meta-analyses were identified from the biomedical literature via a MEDLINE search (1966-August 2004). Published articles were also cross-referenced for pertinent citations, and recent meeting abstracts were searched for relevant data. All articles identified during the search were evaluated. Preference was given to prospective, randomized, controlled trials that evaluated major cardiovascular endpoints and compared ARBs with ACE inhibitors, active controls, or placebo. The renin-angiotensin system plays a pivotal role in the continuum of cardiovascular disease and represents a major therapeutic target in the treatment of patients at risk for vascular events. While ACE inhibitors have been definitively shown to prevent death and MI, studies with ARBs in similar populations have not reduced these endpoints. In clinical trials that enrolled patients with heart failure, post-MI, diabetes, and hypertension, ARBs did not prevent MI or prolong survival compared with ACE inhibitors, other antihypertensives, or placebo. ACE inhibitors and ARBs should not be considered interchangeable, even among patients with a documented history of ACE inhibitor intolerance. ARBs can be considered a second-line alternative in such patients with the realization that they have not been shown to prevent MI or prolong survival.

Treating Hypertension with Angiotensin II Receptor Blockers

The clinical use of angiotensin II receptor blockers (ARBs) has resulted in the effective and successful treatment of arterial hypertension, and vast experience has been gained by physicians in this original indication over the last years. Furthermore, promising results have been obtained with the use of ARBs in other clinical conditions, such as type 2 diabetes mellitus with nephropathy, atrial fibrillation, acute myocardial infarction complicated by left ventricular dysfunction and congestive heart failure. On the basis of the available evidence, some representative molecules of this class have been approved for other indications in addition to hypertension in many countries, and many large clinical investigations are underway to confirm the current indications and, even more importantly, to explore whether these compounds may be effectively used in other conditions. The evidence that ARBs can have benefits at any stage of the cardiovascular disease continuum underlies the potential beneficial effects of these agents — independent of blood pressure reduction — in a wide variety of patients at risk of cardiovascular major events.

The burden of cardiovascular disease: following the link from hypertension to myocardial infarction and heart failure

Cardiovascular disease (CVD) is an enormous health care burden in the United States (US) and is responsible for approximately 40% of all US deaths annually. Heart failure (HF) represents the final stage of the continuum of CVD and is increasing in incidence. Between 1970 and 2000, hospital discharges for HF in the US increased 145%. This trend appears to be related to rising life expectancy and the aging of the population. Once HF develops, the long-term prognosis continues to be dismal. Hypertension is a major risk factor for CVD and the most common risk factor for the development of HF. The results of clinical trials such as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) have helped to clarify the importance of optimizing antihypertensive therapy to reduce CVD risks and development of HF. The trial also confirmed the need for multiple antihypertensive medications to reach recommended blood pressure (BP) goals in most patients. Aggressive lowering of BP is critical to help reduce the risk of CVD and help prevent the development of HF.

Sex-related differences in heart failure

Heart failure (HF) is a complex syndrome that is generally defined as cardiac output not adequate to meet the circulatory demands of the body. HF is at the end of the continuum of cardiovascular disease and preceded by an initiating event such as myocardial infarction, untreated hypertension, idiopathic cause, congenital heart disease, or pulmonary hypertension. In recent years, research has revealed differences in various aspects of HF between men and women including risk factors, pathophysiology, clinical manifestations, and response to treatment. Therefore, the purpose of this review is to review these sex-related differences between men and women who live with HF.

Evolution of calcium antagonists: past, present, and future.

Calcium antagonists were originally introduced as fast-acting vasodilators exhibiting powerful antihypertensive properties. They have now evolved into agents exhibiting a smooth onset and a long duration of action. Early agents, because of their rapid onset of action, were associated with a host of compensatory hemodynamic adverse effects including cardioacceleration and sympathetic stimulation. In contrast, the newer agents appear to retain the antihypertensive properties, but with an improved tolerability profile. Across the cardiovascular disease continuum, the presence of diabetes adds to the risk forcardiovascular events. In diabetic patients with hypertension, multiple drug therapy is clearly indicated. Agents such as calcium antagonists that normalize hemodynamics in this patient population might be expected to demonstrate beneficial effects on mortality. Evidence from the Systolic Hypertension in Europe and the Systolic Hypertension in China trials demonstrated over a 50% reduction in total mortality in the diabetic subgroup in patients treated with calcium antagonists. Among the calcium antagonists, particularly among the dihydropyridine subclasses, the efficacy of the drugs has been accompanied by some side effects, in particular pedal edema. The incidence of pedal edema is dose dependent and is the result of vasodilation and intracapillary hypertension. Newer calcium antagonists demonstrate antihypertensive efficacy similar to that of their predecessors but appear to have a reduced propensity to cause edema.

Overview of angiotensin II-receptor antagonists

T renin–angiotensin system is integral to the mechanisms that regulate cardiovascular homeostasis. The renin–angiotensin system has an important role in the pathophysiology of hypertension and heart failure via the vasoconstricting effects of angiotensin II, which sustain elevated blood pressure levels in hypertension and increase afterload in chronic heart failure. Angiotensin II also affects the structure and function of the glomerulus, stimulates the release of aldosterone (causing sodium and water retention), has growth-promoting effects in the myocardium and arterial wall, induces left ventricular hypertrophy, and may mediate proliferative and hypertrophic processes involved in atherosclerosis (Table I).1 Blocking the formation or effects of angiotensin II has important clinical implications for treating cardiovascular diseases and slowing the progression of the cardiovascular disease continuum. The first available class of drugs to affect the renin–angiotensin system was the angiotensin-converting enzyme (ACE) inhibitors. Numerous clinical trials and extensive clinical experience with ACE inhibitors have clearly demonstrated the therapeutic benefits of blocking the conversion of angiotensin I to angiotensin II. More recently, angiotensin II-receptor blockers (ARBs) were introduced for the treatment of hypertension and heart failure. This article provides a brief overview of the pharmacology and clinical use of ARBs with some comparisons to ACE inhibitors.