The studies described above show that modest reductions in blood pressure among patients with mostly stage 1 and 2 hypertension have tremendous benefits. Although we have good data supporting the benefits of reducing systolic blood pressure into the range of 145 mm Hg, we do not know whether the incidence of heart failure can be decreased even more by reducing the blood pressure to the target of < 140/90 mm Hg currently recommended by the Seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) for patients with hypertension who do not have comorbid conditions (47). The Hypertension Optimal Treatment (HOT) trial randomized patients to three different diastolic blood pressure treatment goals: ≤90 mm Hg, ≤85 mm Hg, and ≤80 mm Hg (48). The lowest risk point for major cardiovascular events occurred at 138.5 mm Hg systolic and 82.6 mm Hg diastolic. However, the number of patients who developed heart failure was too small to draw conclusions.

More data are available about the benefits of trying to reach the blood pressure goal of < 130/80 mm Hg recommended by JNC for patients with diabetes. The UK Prospective Diabetes Study (UKPDS) found that patients randomized to tighter blood pressure control (mean, 144/82 mm Hg) versus less-tight control (mean, 154/87 mm Hg) had a 60% lower risk of heart failure (95% CI 20% to 80%) (49). The HOT trial found a 51% lower risk of major cardiovascular events among diabetics randomized to a target of ≤80 mm Hg compared to those with a target of ≤90 mm Hg (48). The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial also showed benefits of tighter blood pressure control, including lower rates of myocardial infarction for patients with hypertension randomized to a target diastolic blood pressure of < 75 mm Hg versus a target of 80 to 89 mm Hg (50). The ABCD Trial also found lower stroke rates among diabetics without a history of hypertension who were randomized to a target diastolic blood pressure 10 mm Hg below their baseline versus a target of 80 to 89 mm Hg. However, the number of cases of incident heart failure was small in these studies and no conclusions could be drawn.

Patients with hypertension who have suffered a stroke are at high risk for other cardiovascular events, and one study suggests that tight blood pressure control in this group may reduce the risk of heart failure. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) patients with prior stroke or transient cerebral ischemia were randomized to placebo or one of two active treatments: the ACE inhibitor perindopril alone or perindopril plus the thiazide diuretic indapamide (51,52). Pretreatment blood pressure was 147/86 mm Hg. Active treatment resulted in a 9/4 mm Hg reduction in blood pressure and a 26% reduction in incident heart failure. The group receiving both the diuretic and the ACE inhibitor had more pronounced blood pressure lowering (12.3/5.0 mm Hg versus 4.9/2.8 mm Hg), and this group had greater reductions in heart failure and major cardiovascular events than did the ACE inhibitor group alone (52,53).

In summary, reducing blood pressure to below 140/90 mm Hg has incremental benefits for reducing heart failure incidence among patients with diabetes and prior stroke. For patients who do not have diabetes or a previous stroke, achieving this blood pressure goal probably reduces cardiovascular disease, although we do not know with certainty whether the incidence of heart failure is also decreased.

The choice of an antihypertensive agent obviously depends on the drug’s ability to reduce overall cardiovascular risk, so choosing an agent because it is best at reducing heart failure risk would make no sense if it is not equally beneficial with respect to other endpoints. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) found that patients treated with the diuretic chlorthalidone, the dihydropyridine CCB amlodipine, and the ACE inhibitor lisinopril had similar rates of cardiovascular events and cardiovascular deaths (54). Meta-analyses have generally reached similar conclusions and other indirect evidence suggests there is a linear relationship between blood pressure reduction and the reduction in cardiovascular events for the most commonly used antihypertensive medications.

Since antihypertensive agents generally result in equivalent rates of cardiovascular events, the antihypertensive drug class that is more successful at preventing heart failure should be preferred over others because of the importance of heart failure as a public health problem. In the ALLHAT study, the 6-year rate of developing heart failure was lowest among patients treated with chlorthalidone (7.7%), intermediate among those treated with lisinopril (8.7%), and highest among those treated with amlodipine (10.2%, p <0.001 for amlodipine and lisinopril compared to chlorthalidone) (54). One meta-analysis that excluded ALLHAT found diuretics to be superior to CCBs for preventing heart failure, but diuretics were not found to be superior compared to ACE inhibitors (39), although other studies have reached different conclusions (55).

β-blockers and adrenergic receptor binders (ARBs) were not included in ALLHAT, so we know much less about these agents. However, a United Kingdom Prospective Diabetes Study (UKPDS) found similar rates of heart failure between the ACE inhibitor captopril and the β-blocker atenolol (56), and the LIFE study found similar rates of heart failure between patients treated with atenolol and the ARB losartan (57). Thus, β-blockers and ARBs are likely to be as beneficial as ACE inhibitors, although their equivalence to diuretics has not been studied.

The ALLHAT trial is the only large, comparative trial of antihypertensive medications that randomized patients to primary treatment with a peripheral α-blocker. The α-blocker arm of the study was terminated early because, compared to treatment with the diuretic cholorthalidone, the group assigned doxazosin had a doubling in heart failure risk as well as a higher risk of stroke (19% increased risk) and combined cardiovascular disease events (25% increased risk) (58). The twofold difference in heart failure observed with doxazosin is comparable in magnitude to the difference seen in early hypertension trials comparing diuretic or β-blocker treatment with placebo. The higher rate of heart failure in the doxazosin group occurred despite only a small blood pressure difference between the diuretic and α-blocker groups (systolic blood pressure 3 mm Hg higher for the doxazosin group). This evidence suggests that blood pressure lowering with a peripheral α-blocker probably has no benefit in reducing heart failure, which is consistent with the results of the VA Cooperative Heart Failure Trial that found the α-blocker prazosin was no more effective than placebo in the treatment of patients with established heart failure (59).

Although debate continues to rage on the optimal firstline antihypertensive, the available evidence suggests that expanding use of thiazide-type diuretics for the treatment of hypertension will help reduce the incidence of heart failure. It is unknown whether diuretics are actually superior at altering the underlying disease processes that lead to ventricular injury and dysfunction, or whether diuretics simply control symptoms of heart failure among patients with early disease. Chlorthalidone and other thiazide-type diuretics appear to achieve similar outcomes for cardiovascular events and mortality but there are no data available for comparative rates of heart failure (60). ACE inhibitors, ARBs, and β-blockers may be somewhat less effective than diuretics, and CCBs and α-blockers are clearly inferior. However, the majority of patients will require more than one drug for blood pressure control, and the optimal therapeutic regimen to prevent heart failure for an individual patient is likely to be the one that lowers blood pressure the most with the least side effects.

Poorly controlled hypertension can eventually lead to LVH, a form of asymptomatic left ventricular dysfunction (Stage B, Fig. 30-1). LVH can ultimately cause symptomatic heart failure due to diastolic dysfunction from poor ventricular compliance (Stage C, Fig. 30-1). When present, LVH portends a worse cardiovascular prognosis overall and an increased risk of heart failure (13). Strict control of hypertension is, therefore, extremely important for individuals with LVH. Reduction of left ventricular mass has been observed in patients receiving antihypertensive drug treatment (except for the direct vasodilators) (61,62), and the declining prevalence of severe hypertension and LVH corresponds well with increased use of antihypertensive medications (63). Lifestyle modifications to promote weight loss, reduce salt intake, and increase physical activity also reduce LV mass (64). Furthermore, the regression or lack of development of LVH while taking antihypertensive therapy is a favorable prognostic sign (65,66). There is, however, insufficient clinical evidence to warrant using an individual patient’s change in LV mass to guide therapeutic decision making.

It is uncertain whether some antihypertensive medications are better than others for preventing heart failure among patients with LVH. There are theoretical reasons to choose drugs that block the renin-angiotensin-aldosterone system (RAAS) since these agents may have neurohumoral antihypertrophic effects on LV mass that are independent of blood pressure lowering. However, the Treatment of Mild Hypertension Study (TOMHS) does not support this hypothesis. In this trial, individuals with mild hypertension were randomized to placebo, acebutolol, amlodipine, chlorthalidone, doxazosin, or enalapril. All patients received a lifestyle intervention to promote increased physical activity, reduction in salt intake, and weight loss. After 1 year, the groups assigned the thiazide diuretic and the CCB had significantly greater reductions in LV mass than the β-blocker, ACE inhibitor, α-blocker, and placebo groups (64). A meta-analysis of predominantly small studies that excluded TOMHS suggested that LV mass was reduced to a greater extent in patients treated with CCBs, ACE inhibitors, and ARBs compared to β-blockers. Diuretics did not significantly differ from any of the other medication classes (61). In the Losartan Intervention for Endpoint Reduction in Hypertension Study, a large trial in which all participants had LVH by electrocardiogram (ECG) criteria, the ARB losartan reduced LVH more than atenolol and major cardiovascular events were also reduced (57,67). Notably, incident heart failure was similar in both groups. One explanation for this finding is that atenolol slows the heart rate and allows more time in diastole for filling. Thus, even though atenolol had a less-beneficial effect on LVH regression, its other cardiac and neurohormonal effects may have helped prevent heart failure through other pathways, ultimately resulting in equal benefits compared to losartan.

We believe that the debate about which single drug is best for promoting regression of LVH and preventing heart failure is misguided because it directs our attention away from the central clinical problem. Most patients with LVH have blood pressure that is hard to control and will require multiple medications. The main goal for patients with LVH should be to reduce the blood pressure to recommended targets (i.e., <140/90 mm Hg) with whatever combination of medications is effective, tolerated, and affordable for a given patient. We are unaware of any studies that have compared different combinations of drugs to see which are most effective at reducing incident heart failure. Based on
the limited amount of data previously described, a reasonable approach would be to start with a combination of a thiazide-type diuretic and either an ACE inhibitor or an ARB and then add a β-blocker or a CCB as needed to reach the appropriate blood pressure target.

Control of hyperlipidemia prevents CAD and myocardial infarction (MI) and in some studies has been proven to reduce the incidence of heart failure. Cholesterol-lowering therapy with a statin in patients with CAD, in addition to the beneficial effects on other cardiovascular events and mortality, has been proven to reduce incident heart failure by 20% in the Scandinavian Simvasatin Survival Study (absolute risk reduction 2% over 5 years) (71). In the A to Z Trial, performed in patients with acute coronary syndromes, high-intensity statin therapy was associated with a 28% reduction in heart failure compared with lower-intensity statin therapy (1.3% absolute risk reduction over 2 years) (72). Reduction in heart failure is not limited to treatment with statins. Use of gemfibrozil in the Veterans’ Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial reduced the rate of heart failure hospitalization in men with CAD by 22% (2.7% absolute risk reduction over 5.1 years) (73). Several other lipid-lowering medication studies did not show a significant reduction in heart failure events or did not report heart failure as an outcome. However, these reports very likely underestimate the impact of treating hyperlipidemia on heart failure. Since the primary mechanism by which lipid-lowering agents reduce the incidence of heart failure is by reducing the rate of myocardial infarction, demonstration of a significant reduction in heart failure with lipid-lowering drugs may require larger studies with longer follow-up than what is needed to detect reductions in cardiovascular events.

Patients with established atherosclerotic disease are at increased risk for the development of heart failure. The effects of ACE inhibitors have been tested in patients at high risk of heart failure due to pre-existing cardiovascular disease who had minimal or no elevation in blood pressure. Three large, placebo-controlled trials of ACE inhibitors enrolled predominantly patients with stable CAD without evidence of heart failure (Table 30-2) (74,75,76). Mean baseline blood pressures for these three
trials were 139/79 mm Hg in the Heart Outcomes Prevention Evaluation Study (HOPE), 137/82 mm Hg in the European Trial on Reduction of Cardiac Events with Perindopril in Patients with Stable Coronary Artery Disease (EUROPA) and 133/78 mm Hg in the Prevention of Events with Angiotensin-Converting Enzyme Inhibition Trial (PEACE). Thus, the majority of patients had systolic blood pressure below the recommended target of 140 mm Hg. In these trials, systolic blood pressure was reduced by 3 to 5 mm Hg in the ACE inhibitor groups compared to controls receiving placebo.