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 The recent Antihypertensive and Treatment to Heart the a blocker because it was associated with as of for heart and one more cardiovascular events than as initial therapy. Because there was no placebo however, this study not have the ability to was in these or less effective in reducing cardiovascular events than was the A recent study different antihypertensive agents to placebo some one of six or placebo to a diastolic blood pressure (BP) of less than mm Hg. Investigators evaluated the subjects of the Cooperative Study and compared the BP control rates and effects of treatment placebo in patients with stage 1 or 2 hypertension. the end of the study, 30% of the total participants on placebo achieved a diastolic BP lower than mm Hg, with control rates as high as in older The drug effect rate was for those on placebo, which was similar to the for patients The rates because of high Bps were for patients placebo and for those on therapy. The authors that placebo control important for both the and effects of antihypertensive therapy in trials those with stage 1 and stage 2 et al. blood pressure and effects in the treatment of hypertension. from a of Cooperative Arch Intern Med. 2000; continues over what of studies patients to placebo therapy. In the placebo rates may be close to the rates for effective placebo control is as an essential for new In placebo therapy has been in the effectiveness of for high as well as for and as the the is often stronger in these diseases than in For in studies on may be about as effective as in they about 50% as well as had it not been for the placebo-controlled of the trial, a low-dose would have to favorably affect function in when it was no more effective than The Sixth Report of the Joint National Committee on the Prevention, Detection, and Treatment of High Blood Pressure (JNC VI) that placebo control may be useful in trials 1 and 2 hypertension. authors, however, that it is to have a placebo in studies of antihypertensive therapy, drug therapy has been shown to reduce cardiovascular events. Furthermore, the was recently to that therapies should be against treatment and placebo used only when no effective treatment Now there has been a of the Cooperative study in which on from in patients placebo, with the rate of placebo in the older As in the Treatment of Hypertension Study was more to occur in the effects in a large percentage of with and more often in the placebo than the therapy group. Furthermore, the differences in the rates of of therapy between the and patients were effects often to are not the result of therapy. This can be only with a placebo control group. The is not well and may of If there is no placebo treatment events will be as drug effects and change the of a or Because the risk of a vascular event remains over the duration of most hypertension trials, in patients with stage 1 hypertension mm mm Hg) with no other risk factors or a placebo control group may still have a in hypertension treatment This appears to be in with the of the however, investigators who not that this is even in this low-risk group. recently compared the effectiveness of the calcium channel blocker against a blocker in stroke and cardiovascular morbidity and mortality. They a prospective, randomized, end point trial, hypertensive patients years of with a diastolic blood pressure (BP) of at least mm Hg. They were treated for a mean of years, with a baseline BP of mm Hg. of the patients were randomized to either mg of diltiazem, with an angiotensin-converting enzyme (ACE) inhibitor added as step if diastolic pressure remained above mm Hg, a diuretic or a blocker added in step The other patients were randomized to either a thiazide diuretic or a β blocker, with the two in step In step an ACE inhibitor or an a blocker was added. In both groups, step any antihypertensive agent other than a calcium BP was reduced 3 mm Hg more in the group than in the group mm Hg mm The primary end point of and and other cardiovascular was reduced in both In this trial, were reduced more in the but a 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 continues as to 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, 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 in the study, the of and heart was in the CCB total was similar in the two treatment In all of these trials, it is difficult to the initial therapy in for as at the end of the trial, only 50% of the group remained on compared with 45% in the 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 these trials help to clarify is that including favorably reduce vascular events. on blocker or ACE inhibitor-based treatment is better than a CCB-based results of other such as the For continue to lower BP to the established goal and if all other are the of should a part in

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