Analysis of Recent Papers in Hypertension

Hypertension occurs in about 50% of patients with type 2 diabetes and when the two diseases occur together, the risk of stroke or any cardiovascular event doubles, compared to that if only one of these risk factors is present. Diabetes continues to remain the most common cause for renal dialysis. In diabetics with hypertension, the risk for developing end-stage renal disease (ESRD) is five to six times greater than in the hypertensive without diabetes. Both hypertension and diabetes are more prevalent in the black American and native American communities and contribute to the greater likelihood of these subjects developing ESRD. In 1994, the Working Group Report on Hypertension and Diabetes recommended a blood pressure (BP) goal of <130/85 mm Hg to both preserve renal function and reduce cardiovascular events. This recommendation was supported in the sixth report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). A group of 10 experts recently reviewed previous recommendations on behalf of the Hypertension and Diabetes Executive Working Groups of the National Kidney Foundation. They evaluated recent randomized, double-blind, placebo-controlled studies with at least 3 years of follow-up, as well as recent meta-analyses, to formulate their therapeutic recommendations. They evaluated a total of 12 trials, including the Hypertension Optimal Treatment (HOT) trial, the United Kingdom Prospective Diabetes Study (UKPDS), the Appropriate Blood Pressure Control in Diabetes (ABCD) trial, and the Modification of Diet in Renal Disease (MDRD) trial, and concluded that lowering the previous blood pressure goal level recommendation from 130/85 mm Hg to 130/80 mm Hg in those with diabetes and/or renal impairment is appropriate on the basis of available data. This level was also adopted by the Canadian Hypertension Society. Furthermore, a BP level of less than 125/75 mm Hg is recommended for people who have greater than 1 g of proteinuria and renal insufficiency, regardless of etiology. To achieve this level of blood pressure control in an effort to both reduce cardiovascular event rates and slow the rate of renal functional decline, clinical trials suggest that at least 65% of patients require two or more different antihypertensive agents. Although angiotensin-converting enzyme (ACE) inhibitors remain the preferred initial therapy, they recommend starting with both an ACE inhibitor and a thiazide diuretic when the systolic pressure must be reduced 15 mm Hg or more. When baseline serum creatinine is <1.8 mg/dL, a thiazide diuretic is indicated; an ACE inhibitor and loop diuretic are more effective when baseline creatinine is above this value. Additional therapies to achieve this goal may include a long-acting calcium channel blocker (CCB). The authors suggest that, when proteinuria is present, a non-dihydropyridine CCB (non-DHPCCB), such as verapamil or diltiazem, may have a more beneficial effect on proteinuria. However, when added to background ACE inhibitor and diuretic therapy, a dihydropyridine CCB (DHPCCB), such as amlodipine, long-acting nifedipine, or felodipine, will reduce both proteinuria and cardiovascular event rates. If Bps are still not at goal, and if the baseline pulse is ≥84 beats per minute, a low-dose β blocker or α/β blocker can be added. If the pulse is <84 beats per minute, add a DHPCCB if a rate-limiting non-DHPCCB was used first and vice-versa. Finally, if still not <130/80 mm Hg, a long- acting α blocker might be added nightly or referring the patient to a hypertension specialist should be considered.—Bakris GL, Williams M, Dworkin L, et al. Preserving Renal Function in Adults with Hypertension and Diabetes: A Consensus Approach. Am J Kidney Dis. 2000; 36(3):646–661. Using a MEDLINE search through June of 1999, Messerli and colleagues evaluated eight prospective, randomized studies of more than 12 months' duration that reported outcome in diabetic hypertensive patients. Evaluating the effect of treatment on morbidity and mortality, the authors reported that all four drug classes, including low-dose diuretics, 8 blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium antagonists, were equally effective in reducing cardiovascular morbidity and mortality. Because more than 60% of patients required more than one drug to control blood pressure, the initial choice of antihypertensive agent assumed less importance. For elderly diabetics, who often have isolated systolic hypertension, however, the meta-analysis suggests that calcium antagonist-based treatment provided good protection against cardiovascular events. The authors support intensive blood pressure control to levels of <130/85 mm Hg, as recommended by JNC 6.—Grossman E, Messerli F, Goldbourt U. High Blood Pressure and Diabetes Mellitus. Are All Antihypertensive Drugs Created Equal? Arch Intern Med. 2000;160:2447–2452. The treatment of hypertension lowers cardiovascular complications to a greater extent in diabetics than in nondiabetics. Although the rate of renal functional decline is three times as great with a systolic BP (SBP) of 140 mm Hg when compared with 130 mm Hg, a soon-to-be-published meta-analysis in nondiabetic renal disease suggests a lower risk of end-stage renal disease or a doubling of the serum creatinine level with an achieved SBP of 110 mm Hg. Nevertheless, the JNC VI recommendation to lower the BP in diabetics to <130/85 mm Hg was not supported by individual trial-based evidence. Now we have these two reports, one a consensus document and one a meta-analysis, both supporting the recommendation to reduce SBP in the diabetic to at least 130 mm Hg. These two reports differ, however, in suggesting that either a diastolic blood pressure of 80 or 85 mm Hg should be achieved. Although the recent HOT trial supports a diastolic goal of 80 mm Hg, this is a departure from the earlier JNC VI recommendation. Even though it is difficult to separate the more favorable BP levels achieved in comparison with placebo, the evidence suggests that an ACE inhibitor should be part of the treatment program, if not the initial agent selected for BP control in the diabetic. An ACE inhibitor, ideally with a diuretic, appears to both preserve renal function and improve cardiovascular outcome. Although the meta-analysis by Grossman et al. suggests parity among low-dose diuretic, β blocker, ACE inhibitor, or CCB therapy, most experts feel that initial blockade of the renin-angiotensin axis with an ACE inhibitor is a more effective strategy to improve cardiovascular outcome. Several studies strongly suggest that an ACE inhibitor-based treatment program is more effective in reducing cardiovascular morbidity and mortality than a CCB-based regimen. However, as two or more agents will often be necessary to achieve goal BP in most diabetics, the initial selection often assumes less importance. When > 15/10 mm Hg BP reduction from baseline is required to achieve goal, the authors of the consensus document appropriately recommend a thiazide-type diuretic, with initial ACE inhibitor therapy when renal function is normal or a loop diuretic when creatinine is > 1.8 mg/dL. Although the consensus document emphasizes a more beneficial reduction in proteinuria with a non-DHPCCB as compared to a DHPCCB, it appropriately states that this difference is of less importance if the patient is already on background ACE inhibitor therapy. Two new concepts in the consensus document are of interest. First, utilizing Framingham Heart Study information in which a resting heart rate of >84 is associated with a worse outcome, use of a β blocker is recommended when the resting heart rate is >84 or when there is another reason to use one. Additionally, the authors support the use of both a DHPCCB and non-DHPCCB together in the same patient because of an additive blood pressure lowering ability, even though there are no evidence-based trials supporting their concomitant use. Control of BP remains a high priority in practice. Although public health policy currently dictates the recommended level for blood pressure control, achieving a BP of 130/80 mm Hg will probably benefit patients more than previously recommended levels of control. The use of ACE inhibitor therapy in combination with a diuretic and other agents assumes a high priority in therapy. The physician community has continually questioned the clinical effectiveness of lifestyle modification alone in the treatment of hypertension. The original Dietary Approaches to Stop Hypertension (DASH) study (n=459; 29% hypertensive) established that a diet high in fruits and vegetables, but low in fat (6% of calories from saturated fat), reduced blood pressure (BP) more effectively than either a control diet or one rich only in fruits and vegetables. To further define the importance of different dietary patterns in the participants with stage 1 hypertension (BP of 140–159 mm Hg and/or diastolic BP of 90–95 mm Hg), the investigators now report on this subgroup of 133 hypertensive participants within the overall trial. After a 3-week control diet, participants (60% female; 65% black) were randomized for 8 weeks to either 1) a control diet, 2) a diet rich in fruits and vegetables but otherwise similar to the control diet, or 3) the DASH diet, combining fruits, vegetables, and low-fat dairy products and including whole grains, fish, poultry, and nuts, and reduced in fats, red meats, sweets, and sugar-containing beverages. With sodium intake and weight held constant throughout the study, the DASH diet more favorably reduced systolic BP (−11.4 mm Hg) and diastolic BP (−5.5 mm Hg) than the fruits-and-vegetables diet (−7.2 mm Hg/−2.8 mm Hg), and both were better than the control diet. Beginning as early as 2 weeks and continuing throughout the 8-week study, 70% of the participants on the DASH diet achieved a BP of <140/90 mm Hg, compared with 45% on the fruits-and-vegetables diet and 23% on the control diet. This result suggests that in patients with mild (stage 1 or grade I) hypertension, the DASH combination diet may be useful in controlling blood pressure and strengthens the recommendation of the JNC sixth report to begin with lifestyle modification in low-risk patients with Stage I hypertension.—Conlin PR, Chow D, Miller III ER, et al., for the DASH Research Group. The effect of dietary patterns on blood pressure control in hypertensive patients; results from the Dietary Approaches to Stop Hypertension (DASH) trial. Am J Hypertens. 2000;13:949–955. The most recent Sixth Report of the Joint National Committee for the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) recommends lifestyle modification alone for 3–6 months in patients with BP of < 160/100 mm Hg, unless they are at high risk for a vascular event (risk group C). Although physicians have been reluctant to embrace this recommendation, the present DASH sub-study specifically addresses this issue, suggesting that nonpharmacologic therapy alone may be effective. Of particular importance was that dietary compliance remained close to 100% throughout the 8-week intervention phase. The public health implications of a diet containing 1200 mg of calcium and 10 servings of fruits and vegetables per day to prevent both osteoporosis and cancer are enormous. Although the exact nutrients responsible for the benefit on BP reduction cannot be directly ascertained from this study, urinary potassium and magnesium excretion were greater in the intervention diets than in the control diet. As pointed out by the authors, an interactive effect among nutrients may quite possibly explain the favorable effect on BP reduction. This was a well performed study. All confounding variables were similar at baseline and there was a large percentage of both minority and female subjects in the study. The differences in BP achieved were controlled for the differences in the control group itself, suggesting that the impressive results in BP reduction are similar to those achieved with most single-agent drug therapy. Although it might be premature to recommend universal adoption of this diet without studying it for a longer period, it appears that we are closer to understanding the importance of lifestyle modification in the treatment of hypertension. Although we remain unsure of our patients' ability to adhere to this diet, and of which nutrients are essential for achieving this benefit, we must continue to emphasize this important message: lifestyle modification may enable us to control hypertension without drug therapy in some cases. Perhaps we should begin with drug therapy and withdraw it as the DASH diet lowers BP and BP control is achieved. An easy-to-prepare and cost-effective means of employing this diet, however, is the next step in this process. A major caveat in the DASH diet study is that this was a feeding trial; all food was provided by the study centers. A more “real world” study might help to clarify what can and cannot be accomplished in clinical practice. With a three-fold greater risk than in men, approximately 40% of women will sustain an osteoporotic fracture over their lifetime. Although large prospective and case-controlled studies have shown that thiazide diuretic therapy is associated with a 30% reduction in hip fracture, no trial has examined the effect of low-dose thiazide treatment on bone mineral density (BMD) at the hip or spine. Furthermore, the trials have not included normotensive men as well as women. Investigators from the Puget Sound Group Health Cooperative in Seattle enrolled 320 normotensive adults, aged 60–79, with normal BMD, into a randomized, double-blind study measuring the effects of hydrochlorothiazide (HCTZ) on the rate of bone loss over 3 years. After enrollment of 205 healthy women and 115 healthy men, 95% of whom were white, participants were randomly assigned to one of three study groups: placebo, 12.5 mg HCTZ, or 25 mg HCTZ per day. All had adequate baseline calcium intake and were encouraged to consume adequate dietary potassium and calcium throughout the study. By means of dual energy x-ray absorptiometry, total as well as hip and spine BMD was measured at baseline and at each 6-month visit. The primary end point was the change in BMD at the hip. Ninety-seven percent completed the 3-year visit. The investigators found a dose-response relationship between HCTZ treatment and the percent change in BMD at the hip. In comparison to placebo, the change in total hip density was 0.79 percentage points with 12.5 mg of HCTZ and 0.92 percentage points in the 25-mg group. Treatment effects were stronger in women than in men. No difference was noted among the groups for spine or total-body BMD. Rates of fracture occurrence were too infrequent to be evaluated.—LaCroix AZ,Ott SM, Ichikawa L, et al. Low-dose hydrochlorothiazide and preservation of bone mineral density in older adults. Ann Intern Med. 2000;133:515–526. This 3-year, randomized, controlled trial with low-dose HCTZ treatment in healthy, normotensive older people is the first trial to show that low-dose HCTZ prevented loss of BMD at the hip. Although the magnitude of the benefit was modest, it was consistent in both men and women and at both doses. In addition, mean urinary calcium excretion decreased in both the 12.5-mg and 25-mg HCTZ groups, suggesting a mechanism for the benefit. More patients (22) in the 25-mg group required potassium supplementation than in the 12.5-mg (3) or placebo (1) groups, emphasizing the importance of following serum potassium levels. Although low-dose HCTZ continues to be recommended to prevent both cerebrovascular and cardiovascular events in patients with hypertension, it is nice to learn of this added benefit on BMD for those on diuretic therapy. As the authors suggest, the modest benefits found at 3 years, if followed over 10–20 years of use, might explain the one third reduction in risk for hip fracture observed with thiazide use. Low-dose thiazide diuretics would appear to favorably affect the risk of osteoporotic fracture. Until further studies are completed, additional strategies to prevent fracture rates should be used in those at risk, even if they are already being treated with low-dose thiazide therapy. Because the treatment of hypertension has been shown to be so effective in reducing vascular risk, there continues to be significant controversy over the appropriateness of using placebo controls in clinical trials. The recent Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) stopped the a blocker arm involving doxazosin (Cardura®) because it was associated with twice as many episodes of hospitalization for heart failure and one quarter more cardiovascular events than chlorthalidone as initial therapy. Because there was no placebo arm, however, this study did not have the ability to determine whether doxazosin was actually harmful in these patients, or merely less effective in reducing cardiovascular events than was the diuretic. A recent multidrug study comparing different antihypertensive agents to placebo disclosed some interesting findings. Participants received one of six active drugs (n=1105) or placebo (n=187) to maintain a diastolic blood pressure (BP) of less than 95 mm Hg. Investigators evaluated the 1292 subjects of the Veterans Affairs Cooperative Study and compared the BP control rates and adverse effects of active treatment vs. placebo in patients with stage 1 or 2 hypertension. At the end of the study, 30% of the total participants on placebo achieved a diastolic BP lower than 90 mm Hg, with control rates as high as 38% in older whites. The adverse drug effect discontinuation rate was 13% for those on placebo, which was similar to the 12% for patients receiving active treatment. The discontinuation rates because of extremely high Bps were 14% for patients receiving placebo and 7% for those on active therapy. The authors believe that placebo control provides “an important benchmark” for both the efficacy and adverse effects of antihypertensive therapy in trials involving those with stage 1 and stage 2 hypertension.—Preston RA, Materson BJ, Reda DJ, et al. Placebo-associated blood pressure response and adverse effects in the treatment of hypertension. Observations from a Department of Veterans Affairs Cooperative Study. Arch Intern Med. 2000; 160:1449–1454. Debate continues over what kinds of studies justify subjecting patients to placebo therapy. In situations where the placebo response rates may be close to the response rates for effective therapies, placebo control is regarded as an essential tool for evaluating new drugs. In fact, placebo therapy has always been helpful in evaluating the effectiveness of treatments for high BP, as well as for depression and pain, as the the “placebo effect” is often stronger in these diseases than in others. For example, in studies on depression, placebos may be about 75% as effective as antidepressant drugs; in pain studies, they work about 50% as well as active pain relievers. Recently, had it not been for the placebo-controlled design of the trial, a low-dose testosterone patch would have appeared to favorably affect sexual function in oophorectomized women, when it was actually no more effective than placebo. The Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VI) stated that placebo control may be useful in trials involving stages 1 and 2 hypertension. Some authors, however, believe that it is unethical to have a long-term placebo arm in studies of antihypertensive therapy, where active drug therapy has repeatedly been shown to reduce cardiovascular events. Furthermore, the Helsinki Declaration was recently revised to state that experimental therapies should always be tested against “best current” treatment and placebo used only when no effective treatment exists. Now there has been a re-examination of the Veterans Administration Cooperative monotherapy study in which 1-year response rates, depending on age-race subgroups, ranged from 23%–38% in patients receiving placebo, with the highest rate of placebo response in the older white subgroup. As in the Treatment of Mild Hypertension Study (TOMHS), where depression was more likely to occur in the placebo-treated patients, adverse side effects occurred in a large percentage of placebo-treated patients, with headache and joint pain occurring more often in the placebo than the active therapy group. Furthermore, the differences in the rates of discontinuation of therapy between the active and placebo-treated patients were similar. Side effects often attributed to medication are not always the result of specific therapy. This fact can be recognized only with a placebo control group. The placebo-associated response is not well understood and may consist of several components. If there is no placebo treatment arm, non-drug-related events will be counted as drug effects and change the perception of a medication's safety or usefulness. Because the risk of a vascular event remains minimal over the 3–5-year duration of most hypertension trials, in patients with stage 1 hypertension (140/90 mm Hg-160/100 mm Hg) with no other risk factors or comorbid conditions, a placebo control group may still have a place in hypertension treatment trials. This appears to be in keeping with the principals of the Helsinki Declaration. There are, however, many investigators who do not believe that this approach is justified, even in this low-risk group. Scandinavian researchers recently compared the effectiveness of the calcium channel blocker (CCB) diltiazem against a diuretic/β blocker (D/BB) regimen in preventing stroke and cardiovascular morbidity and mortality. They conducted a prospective, randomized, open, blinded end point (PROBE) trial, enrolling 10,888 untreated hypertensive patients 50–74 years of age with a diastolic blood pressure (BP) of at least 100 mm Hg. They were treated for a mean follow-up of 4.5 years, with a baseline BP of 173/106 mm Hg. One half of the patients were randomized to either 180–360 mg of diltiazem, with an angiotensin-converting enzyme (ACE) inhibitor added as step 2, and, if diastolic pressure remained above 90 mm Hg, a diuretic or a blocker added in step 3. The other 5471 patients were randomized to either a thiazide diuretic or a β blocker, with the two combined in step 2. In step 3, an ACE inhibitor or an a blocker was added. In both groups, step 4 allowed any antihypertensive agent other than a calcium antagonist. Systolic BP was reduced 3 mm Hg more in the D/BB group than in the diltiazem group (to 152 mm Hg vs. 149 mm Hg). The combined primary end point of fatal and nonfatal stroke, myocardial infarction, and other cardiovascular death was similarly reduced in both groups. In this trial, strokes were reduced more in the diltiazem group, but a nonsignificant an in heart disease events was also noted in the CCB L, et al. trial of effects of calcium compared with diuretics and β on cardiovascular morbidity and mortality in The Study. continues as to whether antihypertensive such as a greater benefit in reducing the risk of stroke and cardiovascular disease than such as diuretics and β with the recent as a in Hypertension Treatment trial, comparing the long-acting of to a combination of hydrochlorothiazide and the study above that no trial completed to has of to diuretics and 8 In fact, in the study, the of myocardial and heart failure was in the CCB group, total was similar in the two treatment In all of these trials, it is difficult to the initial therapy in for example, as at the end of the trial, only 50% of the diltiazem group remained on compared with 45% in the diuretic/β blocker group. With so additive therapy used in both groups to achieve a diastolic BP of mm Hg, it is to we end point in these trials. these trials do help to clarify is that therapies, including favorably reduce vascular events. on whether diuretic/β blocker or ACE inhibitor-based treatment is better than a CCB-based regimen results of other studies, such as the trials. For continue to lower BP to the established goal and if all other are the of should a part in

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