Analysis of Recent Papers in Hypertension
Jan Basile, MD, Senior Editor

Abstract

The American Heart Association (AHA) Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention recently published a scientific statement on the “Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease.” The goal of this scientific statement was to make recommendations for the treatment of high blood pressure (BP) in adult men and women either with or at risk for ischemic heart disease (IHD). In making these first-ever recommendations, the authors attempted to synthesize and summarize the best available evidence; where data were meager or lacking, the authors have proposed consensus recommendations. Recommendations are provided for patients in the following 6 categories: General coronary artery disease (CAD) prevention High CAD risk, defined as the presence of diabetes mellitus, chronic kidney disease (CKD), CAD equivalents (carotid disease, peripheral arterial disease [PAD], abdominal aortic aneurysm [AAA]), or calculated 10-year Framingham Risk Score (FRS) of at least 10% Stable angina Unstable angina/non-ST elevation myocardial infarction (UA/NSTEMI) ST-segment elevation myocardial infarction (STEMI) Left ventricular (LV) dysfunction For most adults with hypertension, a BP target of <140/90 mm Hg is recommended for general CAD prevention (category 1). For patients with high CAD risk (as defined above), stable angina, UA/NSTEMI, and STEMI (categories 2–5), however, the recommended BP target is <130/80 mm Hg. For those with LV dysfunction (category 6), the recommended BP target is <120/80 mm Hg. Additionally, in patients with established CAD and LV dysfunction, the BP should be lowered slowly, and caution is advised in reducing diastolic BP below 60 mm Hg, especially in older individuals and those with diabetes. Each BP target was considered a class IIa recommendation, meaning that the weight of evidence/opinion is in favor of usefulness/efficacy, with level of evidence of B (data derived from a single randomized trial or nonrandomized studies) or C (only consensus opinion of experts, case studies, or standard of care exists). The second set of recommendations deals with indications for specific classes of antihypertensive medication. For primary prevention and high-CAD risk patients, an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), calcium channel blocker (CCB), thiazide-type diuretic, or combination is recommended as initial therapy. This is a class I recommendation, meaning there is evidence and/or general agreement of benefit, usefulness, and effectiveness, with level of evidence A (data derived from multiple randomized clinical trials or meta-analyses). In patients with stable angina, UA/NSTEMI, and STEMI, these recommendations call for use of a β-blocker and either an ACE inhibitor or ARB (class I; level of evidence A for most with some class IIa and/or level of evidence B). If a β-blocker is contraindicated or not tolerated, the prescriber can substitute a nondihydropyridine CCB (diltiazem or verapamil) if tolerated (class IIa; level of evidence B). If further BP control is needed, thiazide-type diuretics and/or dihydropyridine CCBs (ie, not verapamil or diltiazem) may be added as necessary. For patients with LV dysfunction, initial recommended therapy consists of an ACE inhibitor or ARB, β-blocker, and either thiazide-type or loop diuretic (class I; level of evidence A). Addition of an aldosterone antagonist should be considered in cases of severe heart failure (class I; level of evidence A), and hydralazine/isorsorbide dinitrate should be added in blacks with LV dysfunction and significant heart failure (class I; level of evidence B). The following drugs are contraindicated in patients with LV dysfunction: non-dihyropyridine CCBs (verapamil and diltiazem), clonidine, moxonidine, and peripheral α-blockers (class III; level of evidence B for most). These guidelines provide consensus recommendations for the treatment of adults with elevated BP to prevent or treat IHD. Future research will hopefully allow us to fill in some of the gaps in the current knowledge, especially as it pertains to target BP in which the strength of recommendation and level of evidence remains relatively low.—Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation. 2007;115:2761–2788. The authors of this scientific statement have done a commendable job of evaluating and summarizing the available data and developing a consensus opinion regarding the management of high BP to prevent IHD or treat individuals with underlying IHD. Of note, there are a couple of key areas in which the recommendations differ from those of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). The new guideline has significantly increased the number of patients eligible for more aggressive BP targets. JNC 7 recommends a BP goal of <140/90 mm Hg in all patients with hypertension except those with diabetes or chronic kidney disease, for whom the recommended BP target is <130/80 mm Hg. The current scientific statement from the AHA has added patients with known CAD, carotid disease, PAD, or AAA, and with a calculated 10-year FRS of at least 10% to the group of high-risk patients with a BP target of <130/80 mm Hg. In addition, the statement recommends that the clinician “consider” a BP target of <120/80 mm Hg in patients with LV dysfunction of ischemic origin. The authors rightfully point out that these recommendations are being made despite the fact that there are no published clinical trials that have randomized patients with IHD to any specific goal BP. Therefore, to justify these more aggressive BP goals, the authors cite 3 main sources of evidence. First is the well-known observational data demonstrating that after correcting for age and other CAD risk factors, patients with lower observed BP have fewer IHD events. Second is the subgroup analysis using intravascular ultrasound from the Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) trial, in which subjects who achieved a BP <120/80 mm Hg had a mean decrease in coronary atheroma volume compared with prehypertensive subjects (BP 120–139/80–89 mm Hg) who had no change in atheroma volume, and hypertensive subjects (BP >140/90 mm Hg) who had a mean increase in atheroma volume. Third is the lack of a consistent, significant J-curve phenomenon (ie, increased event rates at lower BP) seen in clinical trials of patients with and without established CAD. Because of the lack of quality (class I) clinical trial evidence, these recommendations on target BP in higher risk individuals will be met with controversy. The preponderance of available data based on pathophysiologic principles, epidemiologic observation, and sound clinical judgment supports treating patients with established CAD and AAA to a target BP <130/80 mm Hg. In addition, with the high incidence of latent CAD seen in angiographic and autopsy studies in those with significant carotid artery disease and PAD, it also seems reasonable to treat those patients to a goal BP <130/80 mm Hg. However, given the lack of data, it is more difficult to defend a target BP <130/80 mm Hg for those with a calculated FRS ≥10% for the primary prevention of IHD. An elevated FRS has not been a primary inclusion criterion for any major randomized clinical trial of antihypertensive therapy, and there has been no subgroup analysis of a major randomized clinical trial that has shown benefit for more aggressive BP treatment in these very individuals. While this patient population may be at higher risk of developing IHD than other patients with essential hypertension, no data exist to show that treating BP to a more aggressive target than <140/90 mm Hg will lead to better outcomes, and no current consensus or community standard of care supports this recommendation. According to these recommendations, each of the following hypothetical patients would have a BP goal <130/80 mm Hg: 57-year-old male nonsmoker with a total cholesterol level of 220 mg/dL, high-density lipoprotein cholesterol of 45 mg/dL, and untreated systolic BP of 150 mm Hg (FRS=12%) 67-year-old female nonsmoker with a total cholesterol level of 260 mg/dL, high-density lipoprotein cholesterol of 45 mg/dL, and untreated systolic BP >160 mm Hg (FRS=11%) 47-year-old male smoker with a total cholesterol level of 220 mg/dL, high-density lipoprotein cholesterol of 55 mg/dL, and untreated BP of 145 mm Hg (FRS=16%) It is also important to remember that the FRS measures the risk of myocardial infarction or cardiovascular (CV) death, neither of which are the end points most strongly associated with antihypertensive treatment. Meta-analyses of previous randomized, placebo-controlled clinical trials of antihypertensive therapy demonstrate a greater effect on the incidence of stroke and heart failure than on myocardial infarction or CV death. The call for more aggressive BP goals in people with an FRS ≥10% may be an attempt on the part of the AHA to unify recommendations for high-risk primary prevention patients. Recent guidelines from the National Cholesterol Education Program, which have been adopted by the AHA in their recommendations for the primary prevention of CAD, describe patients with at least 2 risk factors for coronary heart disease and an FRS of 10% to 20% as a moderately high-risk category, in which more aggressive lipid-lowering therapy may be indicated. Although consensus may have been reached on the need for more aggressive lipid-lowering treatment in this patient population, a similar consensus does not exist to treat BP more aggressively. The inclusion of patients with an FRS ≥10% would greatly increase the number of patients with a goal BP <130/80 mm Hg. While this intuitively would appear to reduce the number of strokes, heart attacks, and kidney failure, this goal also exposes these patients to the potential adverse effects of additional medications and cost without clear benefit. Interestingly, patients with a history of stroke or transient ischemic attack were not included among patients with a goal BP <130/80 mm Hg. Instead, individuals with carotid artery disease (carotid bruit or abnormal carotid ultrasound or angiography findings) are included. This omission is likely because the current guidelines are designed to specifically address risk of IHD and not recurrent cerebrovascular disease. However, the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) found that more aggressive BP reduction in those with previous stroke or transient ischemic attack resulted in not only fewer recurrent cerebrovascular events but also fewer IHD events. Subjects randomized to perinodopril plus a thiazide-type diuretic achieved a BP around 135/80 mm Hg (a reduction in BP of 12/5 mm Hg from baseline). This resulted in a 43% reduction in recurrent stroke (primary end point), as well as a 40% reduction in major vascular events and a 42% reduction in nonfatal myocardial infarction compared with control participants treated with neither medication. Future recommendations should consider previous stroke or transient ischemic attack as an indication for more aggressive BP lowering to decrease future risk of IHD. The other significant departure from JNC 7 in this AHA scientific statement is the indication for specific medications in the primary prevention of IHD. For primary prevention patients, including those with high CAD risk, therapy with an ACE inhibitor, ARB, CCB, thiazide-type diuretic, or a combination is recommended as initial therapy. As in the recent National Institute for Health and Clinical Excellence (NICE) guidelines from the United Kingdom, notably excluded from this list is β-blocker therapy. The evidence for a reduction in CV end points with β-blocker therapy as a primary prevention strategy is relatively weak, especially in older patients. Of course, most of the studies have used atenolol, making it difficult to extrapolate their results to the entire β-blocker class. Although the β-blocker class remains the most heterogeneous of all classes of CV medications, in the absence of future clinical trials demonstrating at least an equivalent reduction in CV events to that seen with other established classes of antihypertensive medications, β-blocker therapy should not be used as initial therapy in patients with hypertension unless they have established CAD. The current scientific statement uses strong scientific evidence for the initial choice of antihypertensive drug class in different patient populations, with class I recommendations and level of evidence A for most situations. Data supporting different BP targets, however, are much weaker, at best class IIa with level of evidence B or C in most situations. Given this lack of data, significant controversy will continue over appropriate BP targets among different patient populations at risk for and with underlying IHD. The current scientific statement should act as a call for shifting the focus of research in hypertension away from questions of drug selection and toward determining appropriate BP targets in different patient populations in an effort to further improve patient outcome.