Hypertension 2001: Pearls for the Clinician. (Featured CME Topic: Hypertension).

Beginning in 1977 and every 4 years since then, the Joint National Committee (JNC) has published a consensus document for the clinician caring for patients with high blood pressure. Originally scheduled to be published in 2001, the National Heart, Lung, and Blood Institute has suspended publication of the seventh JNC report until the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) Trial is completed in 2002. This paper will highlight some of the clinical advances that have occurred since the sixth report of the JNC on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) was published in 1997. It will provide some clinical pearls to enable the clinician to better care for those individuals with high blood pressure. JNC VII will remain evidence-based in its recommended goals for blood pressure reduction. Where clinical trials do not provide the evidence for the recommended blood pressure goals, epidemiologic observation will guide therapy (Table).

THE ROLE OF LIFESTYLE MODIFICATION

The Dietary Approaches to Stop Hypertension (DASH) study, included in the JNC VI report, (1) established that a diet high in fruits, vegetables, and low-fat dairy products reduced blood pressure more effectively than a typical American diet. To further define the importance of sodium restriction, which was held constant in the original DASH study, the recent DASH-sodium trial randomized subjects to the original DASH (D) diet or a control (C) diet with variable amounts of dietary salt. (2)

Compared with the high-sodium C diet (approximately 3.3 g sodium)-the amount consumed in a typical US diet-the low-sodium D diet (approximately 1.5 g sodium) lowered systolic blood pressure by 8.9 mm Hg and diastolic blood pressure by 4.5 mm Hg. The DASH-sodium trial, however, was a feeding trial, since all foods were supplied by the study centers. Since the control of dietary intake and the almost perfect dietary compliance allowed the investigators to study the true biologic effects of this diet, the ability to sustain this diet over the long term and translate this diet into our clinical practice remains a clinical challenge. Physicians realize the importance of a diet high in fruits and vegetables and low in fat but have been unable to embrace this recommendation and have searched for an easy-to-prepare and cost-effective means of employing this diet. Until we develop an easy-to-use plan that patients can adopt into their life-style, which includes exercise, weight loss, as well as diet, we will be unable to achieve the proven life-style modifications that may help prevent and better control high blood pressure with or without drug therapy.

ISOLATED SYSTOLIC HYPERTENSION

Isolated systolic hypertension (ISH) is defined as a systolic blood pressure (SBP) [greater than or equal to]140 mm Hg and a diastolic blood pressure (DBP) <90 mm Hg. It represents the most common form of hypertension in those older than 60 years and is present in three fourths of those older than 75 years. (3) It will continue to get the appropriate emphasis that it deserves in the next JNC report.

In younger populations, both increasing DBP and SBP are independently associated with cardiovascular risk. At age 60, however, as vascular compliance is reduced, an increasing SBP and a lower DBP (ie, a wider pulse pressure [PP]) is more predictive of risk. Accordingly, PP is a stronger predictor of cardiovascular risk than either SBP or DBP in the older patient. (4) Because there have been no clinical trials in which PP narrowing has been targeted as a means of lessening vascular risk, SBP reduction will continue to be targeted in the older hypertensive patient as in the previous JNC report.

The benefits of treating SBP have been well documented. Several trials (5,6) have shown significant benefit when treating elderly patients with ISFI (SBP >150 or 160 mm Hg, DBP <90 mm Hg). When SBP was reduced by at least 20 mm Hg and to a systolic blood pressure <160 mm Hg (5) or <150 mm Hg, (6) a 35% to 40% reduction in stroke, a 50% reduction in heart failure, a 16% reduction in coronary events, and a 10% to 15% reduction in mortality were realized. Although none of the trials achieved a SBP <140 mm Hg, observational analysis of epidemiologic data suggests that a further improvement in outcome should occur when this goal is achieved. Physicians should therefore try to lower SBP to <140 mm Hg. If untoward side effects limit the ability to reach this goal, a reduction from baseline of at least 20 mm Hg and as close to the target of 140 mm Hg should be pursued. (7)

A recent retrospective analysis of the Systolic Hypertension in the Elderly (SHEP) program (8) found that 7% of the participants taking chlorthalidone had hypokalemia (K + <3.5 mEq/L) at the 1-year visit. Since those who were hypokalemia had no more benefit than the placebo group, if a diuretic is used to treat ISH, potassium levels should be monitored and kept normal.

RECENT CLINICAL TRIALS: THE PLAYING FIELD APPEARS MORE LEVEL

It has been well documented from multiple randomized, controlled trials that the effective control of hypertension reduces the incidence of cardiovascular morbidity and mortality. What has been controversial, however, is whether specific antihypertensive agents differ in their ability to lower this risk. Since JNC VI, several trials have suggested that the initial agent chosen may not have a unique status for reducing event rates except in those with diabetes mellitus.

The open-labeled Captopril Prevention Program (CAPPP) did not show an overall difference in outcome when comparing captopril with diuretics and [beta]-blockers, except in the 5% of diabetics in which cardiovascular event rates were less with captopril. (9) In the recent Swedish Trial in Old Patients with Hypertension (STOP-2), 6,614 patients at least 70 years of age were randomized into three equal treatment groups. Comparison of ACE inhibitors and calcium antagonists with standard diuretic and/or [beta]-blocker therapy showed no difference between the three treatment groups in either the blood pressure achieved or the combined end points of fatal and nonfatal cardiovascular events. (10) The open-labeled Nordic Diltiazem (NORDIL) trial showed a similar rate for the primary outcome of combined fatal and nonfatal stroke, myocardial infarction (MI), and CVD death comparing diltiazem with diuretic and/or [beta]-blocker therapy. (11) The double-blind INSIGHT trial also reported that nifedipine GITS and diuretic t herapy had similar cardiovascular disease outcomes. (12)

CALCIUM CHANNEL BLOCKER (CCB): FRIEND OR FOE

Over the past few years, debate has continued over the appropriateness of calcium antagonists as initial therapy in the treatment of hypertension. Since the last JNC report, the debate intensified with the publication of two meta-analyses. While confirming the benefits of diuretics, [beta]-blockers, and ACE inhibitors on cardiovascular outcomes, they reached different conclusions about effects of calcium antagonists.

In addition to finding the risk of stroke 10% lower in the CCB group, the Pahor analysis (13) found the rates of CV disease mortality and all-cause mortality similar to those of other classes of antihypertensive drugs. The risk of MI and CHF, however, was increased in those on CCB therapy, suggesting to these authors that a CCB should not be used as a first-line agent in the treatment of hypertension.

The Blood Pressure Lowering Treatment (BPLT) Trialists (14) reached a slightly different conclusion from their meta-analysis: they suggested that overall there was no convincing evidence to suggest a difference between various classes of blood pressure lowering agents in their effects on cardiovascular morbidity or mortality. Although only two trials directly compared ACE inhibitors with CCB therapy, the two trials themselves were divergent and there was no difference in stroke, CV death, or total mortality. The authors concluded that only through the results of further ongoing trials would the "best" initial therapy for the treatment of hypertension be determined.

While it appears that both CCB and ACE inhibitor therapy reduce the risk of cardiovascular mortality and stroke when compared with placebo, information on whether diuretic-, [beta]-blocker-, or ACE inhibitor-based treatment is significantly better than an initial CCB-based regimen awaits results of other studies such as ALLHAT.

WHICH AGENT SHOULD BE THE INITIAL AGENT IN THE TYPE 2 DIABETIC: ACE, ARB, OR BOTH?

The renoprotective benefit of ACE inhibitors as initial therapy in hypertensive patients with type 1 diabetes is well established. Recently, the benefit of angiotensin-receptor blocker (ARB) therapy in the type 2 diabetic with nephropathy was established as well. (15-18) It appears, therefore, that since both of these anihypertensive classes delay the onset of end-stage renal disease, independent of their effect on blood pressure, ARB therapy will join ACE inhibitor therapy as appropriate first-line therapy in the type 2 diabetic.

Since JNC VI was published, the idea of using an ACE inhibitor and ARB together in the hope of improving outcome has generated tremendous interest in the treatment of hypertension. The recent Candesartan arid Lisinopril Microalbuminuria (CALM) study was performed in those with type 2 diabetes. (19) It evaluated whether the ARB, candesartan, and the ACE inhibitor, lisinopril, when used together was more effective in reducing microalbuminuria (MAU) than either agent by itself. In achieving dual blockade of the renin-angiotensin system (RAS), at the level of both the angiotensin-converting enzyme and the angiotensin (ATl) receptor, it found that the reduction in MAU was significant when both agents were used together. Because of the additional reduction in blood pressure achieved when combining both agents, however, it remains unclear if the effects on MAU relate to the more effective blood pressure reduction or more effective blockade of the RAS. Since this study did not evaluate hard clinical end points, such as coronary disease or stroke, the benefit of using these agents together on clinical outcome is unknown. Future studies will determine which additional second agent should be chosen when further blood pressure lowering is necessary to improve the degree of MAU and overall morbidity and mortality in the type 2 diabetic. Until those results are known, therapy with an ACE inhibitor or ARB should be used to lower blood pressure in the type 2 diabetic.

THE ALLHAT TRIAL

The ALLHAT, with 42,448 participants, is the largest randomized, double-blind, active-controlled hypertension trial ever performed. (15) Conducted in individuals 55 years of age and older, it was designed to determine whether the newer classes of drugs (amlodipine, lisinopril, or doxazosin) are superior, equivalent, or inferior to diuretics in lowering the combined incidence of fatal coronary heart disease (CHD) and nonfatal MI. Its strength lies in that it has included large numbers of women and blacks, as well as a high proportion of smokers, diabetics and patients with existing cardiovascular disease (groups that have been underrepresented in previous hypertension studies).

For some drugs, blood pressure lowering and improvement in metabolic parameters are an inadequate marker of health benefit. This issue was specifically addressed by the recently published interim analysis of the same ALLHAT trial when the [alpha]-blocker arm was stopped early because of a 25% greater cardiovascular event rate, as well as a twofold greater risk of heart failure when compared with the diuretic chlorthalidone. (20) Although the selective [alpha]-blocker raises high-density cholesterol and improves insulin resistance, these intermediate effects did not translate into overall improvement in clinical outcome. Accordingly, [alpha]-blocker therapy should not be used as monotherapy in those with hypertension, but its role as additional therapy to improve blood pressure control can be recommended.

MONOTHERAPY WILL OFTEN NOT BE THE FINAL THERAPY: THE 60/90 RULE

The majority of patients will require at least two or more agents to achieve the minimal blood pressure goal of <140/90 mm Hg as recommended in JNC VI. Achieving effective DBP reduction usually occurs as SBP goals are met. This refers to the 60/90 rule. Whereas only 60% of patients have their systolic blood pressure reduced to <140 mm Hg, 90% of patients have their diastolic blood pressure reduced to <90 mm Hg. To improve blood pressure control rates, the dose of the first agent used should be increased until the maximum blood pressure reduction occurs with the fewest side effects. Agents are added or combination drugs are used until the blood pressure goal is attained. In choosing an additional agent, a diuretic is better at preventing the risk of ischemic stroke than a [beta]-blocker, ACE inhibitor, or CCB. (21)

SUMMARY

Diuretics and 13-blockers are presently recommended as first-line therapy for the treatment of uncomplicated hypertension. JNC VII will probably consider ACE inhibitors worthy of this recommendation. In those at high risk for CHD or CHF, the initial use of an [alpha]-blocker or calcium antagonist will be recommended with caution. In those with systolic hypertension, who remain at increased risk of stroke, the initial use of CCB therapy continues to be supported by trial-based evidence. A diuretic, based on outcome-based trials, should be included in most regimens to lower the risk of ischemic stroke. Since most patients will require two or more drugs to control their blood pressure, the initial agent chosen will assume less importance for the practicing physician.

References

(1.) The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997; 157:2413-2446

(2.) Sacks FM, Svetkey LP, Vollmer WM, et al: Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med 2001; 344:3-10

(3.) Black HR: New concepts in hypertension: focus on the elderly. Am Heart J 1998; 135:S2-S7

(4.) Franklin SS, Sutton-Tyrrell K, Belle SH, et al: Is pulse pressure useful in predicting risk for coronary heart disease? the Framingham Heart Study. Circulation 1999; 100:354-360

(5.) SHEP Cooperative Research Group: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1991; 265:3255-3264

(6.) Staessen JA, Fagard R, Thij L, et al: Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. the Systolic Hypertension in Europe (Syst-Eur) Trial investigators. Lancet 1997; 350:757-764

(7.) Izzo JL Jr, Levy D, Black HR: Importance of systolic blood pressure in older Americans. Hypertension 2000; 35:1021-1024

(8.) Franse LV, Pahor M, Di Bari M, et al: Hypokalemia associated with diuretic use and cardiovascular events in the Systolic Hypertension in the Elderly Program. Hypertension 2000; 35:1025-1030

(9.) Hansson L, Lindholm LH, Niskanen L, et al, for the Captopril Prevention Project (CAPPP) Study Group: Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension. Lancet 1999; 353:611-616

(10.) Hansson L, Lindholm LH, Ekborn T, et al, for the STOP-Hypertension-2 Study Group: Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity in the Swedish Trial in Old Patients with Hypertension-2 (STOP-2) Study. Lancet 1999; 354:1751-1756

(11.) Hansson L, Hedner T, Lund-Johansen P, et al, for the NORDIL Study Group: Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) Study. Lancet 2000; 356:359-365

(12.) Brown MJ, Plainer CR, Castaigne A, et al: Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000; 356:366-372

(13.) Pahor M, Psaty BM, Alderman MH, et al: Health outcomes associated with calcium antagonists compared with other first-line antiypertensive therapies: a meta-analysis of randomised controlled trials. Lancet 2000; 356:1949-1954

(14.) Neal B, MacMahon 5, Chapman N: Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists' Collaboration. Lancet 2000; 355:1955-1964

(15.) Grimm RH Jr, Margolis KL, Papademetriou VV et al, for the ALLHAT Collaborative Research Group: Baseline characteristics of participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack trial (ALLHAT). Hypertension 2001; 37:19-27

(16.) Lewis E, Hunsicker L, Clarke W, et al: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851-860

(17.) Brenner B, Cooper M, De Zeeuw D, et al: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Eagl J Med 2001; 345:861-869

(18.) Parving H-H, Lehnert H, Brochner-Mortensen J, et al: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345:870-878

(19.) Mogensen CE, Neldam S, Tikkanen I, et al, for the CALM Study Group: Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the Candesartan and Lisinopril Microalbuminuria (CALM) Study. BMJ 2000; 321:1440-1444

(20.) The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack trial (ALLHAT). JAMA 2000; 283:1967-1975

(21.) Klungel OH, Heckbert SR, Longstreth WT Jr, et al: Antihypertensive drug therapies and the risk of ischemic stroke. Arch Intern Med 2001; 161:37-43

TABLE. Goals for Blood Pressure Reduction

Blood Pressure Level
      (mm Hg)                     Condition

      <140/90         Isolated systolic hypertensio hypertension
      <140/90         Hypertension (systolic/diastolic)
      <130/80         Diabetes
      <130/80         Congestive heart failure
      <130/80         Renal insufficiency
      <125/75         Renal insufficiency and
                      >1 gram proteinuria/24 hours

KEY POINTS

* Sodium restriction causes additional blood pressure lowering to that achieved with a diet high in fruits, vegetables, and low-fat dairy products

* An easy-to-implement plan that incorporates exercise and weight loss needs to be available for the practicing physician.

* Attempts should be made to lower systolic blood pressure to <140 mm Hg nail patients with systolic hypertension. If not achievable, reducing systolic blood pressure 20 mm Hg from baseline and at least to <160 mm Hg will improve outcome.

* The importance of pulse pressure narrowing is still unclear and will be evaluated in future hypertension trials.

* Unless the patient has underlying coronary disease or heart failure, ACE inhibitor and calcium channel blocker therapy achieves a similar benefit on outcome as diuretics or [beta]-blockers.

* ARB therapy, as well as ACE inhibitor therapy is evidence-based in the hypertensive type 2 diabetic to slow the progression of renal functional decline and delay the need for dialysis.

* The ALLHAT trial will determine whether the newer classes of drugs (amlodipine and lisinopril) are superior, equivalent, or inferior to the diuretic chiorthalidone in the combined incidence of fatal coronary heart disease and nonfatal myocardial infarction.

* Most patients will require two or more drugs to control their blood pressure to the goal of <140/90 mm Hg.

* If a diuretic is used, potassium levels should be monitored and kept normal to improve outcome.