In practice, diuretic therapy often does not control BP elevation. When this occurs, the physician may be undecided as to whether to increase the dosage. Some experts advocate checking the plasma renin activity. If renin activity is low while the patient is on a diuretic, consider increasing the dosage. If renin activity is high with the patient on a diuretic, volume is less likely to be a major contributor to the persisting BP elevation in this individual, and adding an ACE inhibitor or angiotensin receptor blocker (ARB) would seem preferable. It can also be helpful to assess salt intake by measuring urine sodium excretion. Patients who have a high salt intake may require a higher diuretic dosage to control their BP.

One omission from JNC 7 seems to be that no guidance is given for using doses of hydrochlorothiazide (HCTZ) that exceed 25 mg, which some patients need to achieve good BP control. A higher dosage increases the risk of adverse metabolic effects but might be needed in the patient with a high salt intake or in heavy patients. One precaution, though: If a daily dosage above 25 mg is given, a potassium-sparing agent should usually be given with it to reduce the risk of hypokalemia or arrhythmia. Alternatively, 25 mg of HCTZ can be combined with a potassium-sparing agent, such as spironolactone (Aldactone), amiloride (Midamor), or eplerenone (Inspra), to achieve an increased diuretic effect.

Beware of overreliance on the ALLHAT findings

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is one of the most contentious studies on BP lowering ever published. In a recent report based on renal outcomes in high-risk patients with HTN and reduced glomerular filtration rate (GFR), the investigators concluded that amlodipine and lisinopril had no advantages over chlorthalidone in preventing end-stage renal disease or a greater than 50% decrease from baseline in GFR.² Another report was based on data derived from patients with diabetes, impaired fasting glucose, or normoglycemia. The authors concluded that calcium channel blockers (CCBs) and ACE inhibitors offered no advantage over chlorthalidone during first-step antihypertensive therapy in preventing fatal coronary heart disease or nonfatal MI.³

Some HTN specialists, however, have faulted these analyses on several points. Some question the wisdom of extrapolating from a study with a mean follow-up of 4.9 years to outcomes that might occur 20 or 30 years in the future. Another point to consider is that 25 mg of HCTZ, which is used far more often than chlorthalidone (Hygroton, Thalitone), is clearly not as effective as 25 mg of chlorthalidone, the diuretic that was used in the ALLHAT study. Some contend that if HCTZ had been the comparator drug in ALLHAT, the diuretic arm might have been less effective than the ACE inhibitor and CCB arms rather than approximately equivalent.

Another frequently cited limitation of the ALLHAT study design involved the protocol for treating a patient when maximal dosage of the initial drug did not achieve the target BP. In that case, the physician could only add a second-line agent that was not among the drug classes included in ALLHAT. Thus, an ACE inhibitor could not be added to a diuretic, and a diuretic could not be added to an ACE inhibitor. Beta-blockers were the second-line drugs used most often. As a result, drug combinations that would not generally be used in practice, such as an ACE inhibitor combined with a beta-blocker, were overrepresented in this study.

The findings of the family-practice-based Second Australian National Blood Pressure Study (ANBP2) added fuel to the debate. Conducted in more than 6000 patients aged 65 and older, the ANBP2 showed that in older patients ACE inhibitor treatment was associated with better outcomes than treatment with diuretic agents, despite similar BP reductions.⁴ ACE inhibitors may be most effective in patients who are most at risk—in this case, older men—despite often-minimal changes in BP.

Suggestions on multidrug regimens

If you elect to add drugs to an antihypertensive regimen, consider dropping some that might not be contributing significantly to BP control. For example, when you add a third drug, consider discontinuing one of the others once BP control is achieved.

Drugs that are less effective than others as monotherapy may nonetheless be excellent add-ons to a multidrug regimen. Some diuretics are in this category. Alpha₁-blockers may not be optimally effective as single agents, but often provide the needed additional control in a multidrug regimen. For example, in some patients, a beta-blocker given in combination with an alpha₁-blocker can be extremely effective.

Patient adherence to the regimen may be the single most important determinant of success. Always ask whether the patient is taking the medication before assuming that a particular drug or therapy has failed. You might consider asking if certain conditions, such as the cost of drugs or confusion about which drugs to take or when to take them, pose a barrier to compliance. In some patients, the use of drugs that may be dosed once daily may improve adherence to the regimen.

COMPELLING INDICATIONS

TABLE 1 When hypertension is complicated by other conditions

In patients with HTN complicated by concomitant conditions, the bottom line is, do what works. In the experience of HTN experts and as outlined in guidelines, certain drug combinations are more effective than others in lowering BP and preventing CVD, stroke, and other complications (see Table 1). When patients who have concomitant disorders are treated for HTN, the regimens should be formulated in conjunction with guidelines but tailored to the patient's individual needs and response to medication. As physicians know, not all patients respond uniformly or predictably to antihypertensive regimens.

The regimen should include medications that not only lower BP but also protect the kidneys, heart, and brain. Some data suggest that particular classes of drugs are better at preventing a specific outcome than others. ACE inhibitors and ARBs provide a blockade of the renin-angiotensin system that is highly beneficial in patients with diabetes, and these agents may provide a similar benefit for patients with advanced vascular disease. CCBs and diuretics may have an advantage over other classes with regard to stroke prevention.⁵

Finally, in different patients, HTN is driven by different mechanisms. Regardless of guidelines, when the medications match the mechanism of HTN, the patient is more likely to achieve the BP goal and avoid target-organ disease.

Coronary artery disease

The JNC 7 recommends beta-blockers for hypertensive patients in whom stable angina is present, followed by a CCB if necessary to achieve BP goals. The guideline further recommends that if the patient has an acute coronary syndrome, an ACE inhibitor and a beta-blocker constitute initial therapy, with other BP drugs added as required to bring HTN under control.

Again, the use of beta-blocker monotherapy is disputed by many HTN specialists, most recently in a large meta-analysis, which concluded that beta-blocker monotherapy is less effective than other drug classes in primary prevention of MI.⁶ The INternational VErapamil SR-Trandolapril STudy (INVEST), which included 22,000 patients who received the nondihydropyridine CCB verapamil plus the ACE inhibitor trandolapril, provided evidence in favor of combination therapy. The ACE inhibitor was an add-on agent, and this combination was found to be as effective in reducing cardiovascular mortality in patients with HTN and coronary disease as a diuretic/beta-blocker combination regimen.⁷

Post-MI care

Patients recovering from MI who have HTN are candidates for treatment with ACE inhibitors, beta-blockers, and/or aldosterone antagonists. The ACE or ARB reduces BP and also protects against left ventricular hypertrophy (LVH) and HF.⁸ Beta-blockers are strongly associated with a reduced risk of subsequent MI and of sudden death and are withheld only in patients with severe heart block and in those with bronchospasm despite the use of bronchodilators. Patients with asthma can usually use a cardioselective beta-blocker, but note that cardioselectivity is relative and decreases as the beta-blocker dosage increases.

Short-acting dihydropyridine CCBs are no longer widely used. A long-acting CCB may be an option as an add-on agent in patients whose BP is inadequately controlled by a regimen that includes an ACE or an ARB, a beta-blocker, and a thiazide diuretic. Of course, careful attention to the lipid profile is mandatory, and aspirin is also recommended for all patients without contraindications.

Heart failure

According to the guideline on HF from the American College of Cardiology, good BP control reduces the risk of HF by 50%.⁹ Data from the Framingham study show that 39% of HF cases in men and 59% in women are due to HTN. For patients who are already in HF, a good outcome is highly dependent on stringent BP control.

Asymptomatic patients are treated with ACE inhibitors and diuretics. Those with symptomatic or end-stage disease are treated with ACE inhibitors or ARBs, beta-blockers, aldosterone blockers, and loop diuretics. The ARBs losartan (Cozaar) and irbesartan (Avapro) have shown good efficacy in controlling BP among patients with HF accompanied by diabetes and nephropathy.^10,11 While CCBs such as diltiazem (Cardizem, Dilacor, Tiazac) and verapamil are contraindicated in HF, longer-acting dihydropyridine CCBs (such as amlodipine [Norvasc] and felodipine [Plendil]) and alpha-blockers, though less effective than other antihypertensives in treating HF, can be very helpful if other agents fail to control BP. Patients with HF also require meticulous attention to the lipid profile.

Chronic kidney disease

HTN develops in most patients with chronic kidney disease, but aggressive treatment of elevated BP slows deterioration of renal function and prevents CVD. These patients often need 3 or 4 drugs to attain their BP goals. In patients with impaired renal function and proteinuria, ACE inhibitors and ARBs offer the best renal protection. Use of a loop diuretic instead of a thiazide diuretic is necessary if renal disease progresses to the point that the GFR is less than 30 mL/min/1.73 m² (or a serum creatinine level of 2.5-3 mg/dL). In patients with advanced renal disease, higher doses of loop diuretics may be needed to control BP.

The risk of end-stage kidney disease is 4 times higher among African Americans than other groups. The African American Study of Kidney Disease and Hypertension (AASK) trial demonstrated that ACE inhibitors effectively slow the decline in GFR. Patients with proteinuria benefited the most from treatment with ramipril.¹² The AASK results also showed that the beta-blocker metoprolol is beneficial in African Americans. Although it was not as effective as the ACE inhibitor, metoprolol also slowed the decline in GFR.

Stroke

In patients with acute thrombotic stroke, efforts to lower BP are usually not recommended unless it exceeds 200/120 mm Hg. After the acute phase has passed, however, HTN is managed aggressively. Combined alpha-beta blockade, as with labetalol (Normodyne, Trandate), can be helpful in patients with resistant HTN.

LVH

ACE inhibitors and ARBs are beneficial in these patients, both for controlling BP and reducing the severity of LVH. Diuretics and CCBs also reverse LVH, but beta-blockers do not. An ACE inhibitor/diuretic or ACE inhibitor/CCB combination is effective in most patients. Other drug classes may be used as necessary to control BP. Hydralazine (Apresoline), however, does not cause regression of LVH and is not used unless the HTN is resistant to other agents. Minoxidil (Loniten) should rarely be used.

Type 2 diabetes

In the spring of 2003, the American College of Physicians (ACP) published clinical guidelines for the treatment of HTN in patients with type 2 diabetes. Notably, the ACP stated that BP control should be the first priority in the care of patients with diabetes because it is more effective than glycemic control in reducing microvascular events. Control of HTN dramatically reduces the risk of cardiovascular events and cardiovascular mortality in patients with diabetes, an effect that is detectable within 4 to 6 years. The BP goal for patients with diabetes is 130/80 mm Hg, and first-choice agents are thiazide diuretics, ARBs, or ACE inhibitors. Second-choice agents in these patients are beta-blockers or CCBs.¹³

Reducing BP reduces risk

Is it worth all the effort and expense? The data seem incontrovertible. Lowering BP to the target range

• Reduces stroke risk by 35% to 40%
• Reduces MI risk by 20% to 25%
• Reduces risk of major cardiovascular events by more than 20%¹
• Prevents the death of 1 in 11 patients with stage 1 hypertension and 1 in 9 patients with stage 2 disease over a 10-year period (with a sustained 12-mm Hg drop in systolic BP).²