Analysis of Recent Papers in Hypertension

Abstract

The Captopril Prevention Project (CAPPP) was the first hypertension trial to evaluate the initial therapeutic effects of an angiotensin-converting-enzyme inhibitor (ACE-I) based regimen on cardiovascular (CV) morbidity and mortality. Reviewed in 1999 (J Clin Hypertens. 1999;1(1):77), it randomized 10,985 male and female Scandinavian patients 25–66 years of age to either a twice-a-day captopril-based regimen (and diuretics, if necessary) or conventional therapy with a diuretic and/or β blocker. A calcium channel antagonist could be added as a third and final agent to reduce diastolic blood pressure (DBP) to at least 90 mm Hg or less. During an average follow-up of 6.1 years, there was no difference between the treatment groups in the frequency of the combined primary end point (fatal and nonfatal myocardial infarction, stroke, and other CV deaths) although there was a 21% reduction in the incidence of new-onset diabetes in the ACE-I based group. One planned sub-analysis of the CAPPP, the purpose of the present paper, was to specifically evaluate the outcome in the 4.9% of the total cohort who had type 2 diabetes. With an initial blood pressure of 163/97 mm Hg and similar baseline characteristics (mean age, 55) as the total cohort, the primary end point occurred 41% less often in the ACE-I treated diabetics than in the conventionally treated diabetic group. While there was no difference in the stroke rate, the difference was entirely attributable to fewer CV events in the ACE-I group, with a 52% reduction in CV death. Analysis of other secondary events favoring captopril found a 46% reduction in total mortality and a 66% reduction in myocardial infarction. There was also less atrial fibrillation and congestive heart failure (CHF). These favorable effects could not be explained by differences in blood pressure, which, on average, tended to be slightly higher in the captopril group after the first year of the trial and which persisted until the end of the study (155.5/89 mm Hg in the captopril group vs. 153.5/88 mm Hg in the conventional group). Although the benefit was more evident in males, it occurred mostly in those with poor glycemic control, and in those with elevated total and low high-density lipoprotein cholesterol values, indices of further metabolic decompensation. The authors conclude that the initial use of captopril is superior to the initial use of a diuretic and/or β-blocker-based regimen in preventing CV events in type 2 diabetic patients with hypertension. ACE-I treatment appears to be most advantageous in those at greater risk, that is, those with metabolic decompensation.—Niskanen L, Hedner T, Hansson L, et al. Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/β-blocker-based treatment regimen. A sub analysis of the Captopril Prevention Project. Diabetes Care. 2001;24:2091–2096. The Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of Hypertension (JNC VI) in 1997 strongly suggested the use of an ACE-I in the diabetic with proteinuria, whereas an ACE-I, diuretic, calcium antagonist, and an α blocker, was recommended in the diabetic without evidence of clinical nephropathy. The results of the above subgroup analysis from the CAPPP suggests that initial treatment with an ACE-I, regardless of the presence of nephropathy, should be recommended in the next JNC report. Although this recommendation seems reasonable, we should first review the statistical power of subgroup analysis as well as the importance that the degree of blood pressure lowering achieved in the diabetic has on CV morbidity. CAPPP is not the first trial where a beneficial effect was seen on the primary end point only in the 5% of the total cohort who were diabetic and not within the entire population studied. In the Hypertension Optimal Treatment (HOT) study, for example, within the 8% of the participants who were diabetic, there was a 51% reduction in CV mortality, the primary end point in those with the lowest blood pressures. This was noted in those who were randomized to a DBP <80 mm Hg compared to those with a DBP <90 mm Hg, whereas there was no benefit on the same end point when the entire study population with similar blood pressure reduction was examined. Diabetics often drive the primary CV end point within a trial, as they remain at higher risk than the overall population who often fail to show benefit. The level of blood pressure reduction achieved May also have special significance when studying hypertensive patients with diabetes. In the United Kingdom Prospective Diabetes Study (UKPDS), there was a 34% reduction in CV events in those with type 2 diabetes randomized to the tightly controlled blood pressure group compared to those less tightly controlled (144/82 mm Hg vs. 154/87 mm Hg). However, within the tightly controlled group, with similar blood pressure reduction, there was no advantage for the initial use of the ACE-I, captopril, over the β blocker, atenolol-based treatment group, on the risk of developing diabetic macrovascular and microvascular complications. UKPDS suggests that when blood pressure in the diabetic is lowered near 80 mm Hg (the current diabetic goal), the initial antihypertensive agent chosen May have less importance than the level of blood pressure reduction achieved. In the CAPPP subgroup analysis, which the authors themselves state should be interpreted with caution, the initial use of an ACE-I compared to a diuretic and/or β blocker regimen was associated with a 41% reduction in CV morbidity and mortality. The DBP achieved in the captopril group, however, was 89 mm Hg, not near the goal of 80 mm Hg achieved in the UKPDS and HOT trials. Furthermore, when DBP was reduced to 68 mm Hg, as in the Systolic Hypertension in the Elderly Program (SHEP), a diuretic and/or β blocker regimen effectively lowered CV morbidity and mortality in the type 2 diabetic subgroup. It appears that when blood pressure is not lowered to the recommended goal of 80 mm Hg, the use of an ACE-I regimen assumes greater importance for the reduction of CV events. The authors of this study suggest that diabetic patients with impaired metabolic control seemed to benefit the most from ACE-I therapy. Therefore, in those type 2 diabetics with metabolic decompensation (poor glycemic and lipid control) and DBPs above the current goal of 80 mm Hg, the use of an ACE-I as initial therapy should be recommended. The results of the Antihypertensive Lipid Lowering Treatment to Prevent Heart Attack Trial (ALL-HAT) comparing the ACE-I, lisinopril, and the calcium channel blocker, amlodipine, with the diuretic, chlorthalidone, as initial therapy in more than 15,000 type 2 diabetics, will better evaluate the importance of the initial agent chosen in this population. Until the results of that trial are released at the end of 2002, it appears that we should attempt to reduce DBP to 80 mm Hg in diabetics, and keep their glucose and lipid levels well controlled. It is important to remember that only 11% of our diabetics with hypertension have their blood pressure reduced to <130/80 mm Hg. The initial antihypertensive agent chosen will rarely be the only agent required to achieve effective blood pressure control in this high-risk group. If an ACE-I is not the initial agent chosen, it should be part of the cocktail of treatment—usually given with a diuretic. Based on the results of the Systolic Hypertension in the Elderly Program (SHEP) and Syst-Eur (Systolic Hypertension in Europe) Trial, the Joint National Committee (JNC) VI recommended a diuretic as preferred, or dihydropyridine calcium antagonist as alternative, initial therapy in stage 2 isolated systolic hypertension (ISH) (systolic blood pressure [SBP] >160 mm Hg and diastolic blood pressure [DBP] <90 mm Hg). Stage 1 ISH (SBP of 140–159 mm Hg and a DBP <90 mm Hg), the most common form of untreated hypertension in older adults, has not been studied; it remains unclear if treatment with this degree of blood pressure elevation is beneficial. As more than one half of these patients will progress to stage 2 ISH, the evaluation of these patients is of importance. In a study undertaken to determine whether the currently recommended initial therapy for stage 2 ISH would be effective in adults with stage 1 ISH, investigators from multiple institutions compared the effects of amlodipine (A), a dihydropyridine calcium antagonist (DHP-CA), chlorthalidone (C), a diuretic, and placebo (P) in adults more than 50 years of age. After a 4-week run in period with placebo, 150 patients were randomized in a double-blind fashion to either 5 mg of A (n=48), 15 mg of C (n=50), or P (n=52). After 4 weeks, if they failed to meet the SBP goal of <140 mm Hg, doses were doubled and continued for 12 weeks. A and C reduced SBP by 14.6±12.2 and 14.0±13.5 mm Hg, respectively. Both were more effective than P (3.4±11.3 mm Hg) but not different from each other. Sixty-seven percent of the A, 69% of the C, and 25% of the P-treated patients reached the SBP goal. All therapies were well tolerated. The results of this study support the equivalent efficacy and safety of A and C for the treatment of stage 1 ISH.—Grimm RH, Black H, Rowen R, et al. Amlodipine vs. chlorthalidone vs. placebo in the treatment of stage 1 isolated systolic hypertension. Am J Hypertens. 2002;15:31–36. ISH is defined as an SBP >140 mm Hg and a DBP <90 mm Hg. It represents the most common form of hypertension in the elderly and its prevalence increases with age, being present in three fourths of those over 75 years of age. Although the vascular risk associated with stage 1 ISH (SBP 140–159 mm Hg/DBP <90 mm Hg) is well established, no antihypertensive trial has been completed to test whether treatment is beneficial. In this trial, investigators compared the DHP-CA, A, and the diuretic, C, and found similar safety and efficacy with the primary end point being blood pressure reduction <140 mm Hg. Although non-pharmacologic therapy, in the form of weight loss and salt restriction, has been shown to favorably reduce blood pressure and decrease the need for antihypertensive therapy in older patients with stage 1 ISH, there is little evidence that non-drug or pharmacologic therapy reduces cardiovascular morbidity and mortality in stage 1 ISH. Ongoing trials evaluating both the treatment and prevention of this most common stage of systolic hypertension are anxiously awaited. Based on the present study, A and C should be included as agents in any cooperative study. Angiotensin II type 1 receptor blockers (ARBs) are the newest class of approved antihypertensive agents with six currently on the market for the treatment of hypertension. They were first approved for use in 1995. ARBs are well tolerated and have a side-effect profile similar to placebo allowing physicians to often use these agents as initial antihypertensive therapy. Industry has therefore been encouraged to develop and market additional agents in this class, hoping that a particular agent May have unique properties within the class. In a multicenter, randomized, double-blind, parallel-group trial conducted at 68 sites in the United States, investigators compared the antihypertensive efficacy of olmesartan (a new ARB) at its starting dose of 20 mg daily, with the recommended starting doses of losartan (50 mg), valsartan (80 mg), and irbesartan (150 mg) in 588 patients with stage 1 and stage 2 hypertension (mean blood pressure 157/104 mm Hg). With a mean age of 52 years, 75% of the patients were white, 14% were black, and 62% male. Using both cuff and ambulatory blood pressure monitoring, there was no difference between agents in cuff SBP after 8 weeks of therapy. The reduction in sitting cuff DBP with olmesartan (11.5 mm Hg) was 16% greater than that with irbesartan (9.9 mm Hg), 40% greater than with losartan (8.2 mg), and 46% greater than with valsartan (7.9 mm Hg). The reduction in ambulatory 24-hour DBP was also greatest with olmesartan (8.5 mm Hg) while 24-hour SBP was lowered more with both olmesartan and irbesartan (12.5 mm Hg and 11.3 mm Hg, respectively) than with either losartan or valsartan. There was no difference among the four drugs in either tolerability or side effects. The authors conclude that the 20-mg starting dose of olmesartan is more effective in reducing cuff DBP than the approved starting doses of losartan, valsartan, or irbesartan in those with stage 1 or stage 2 hypertension.—Oparil S, Williams D, Chrysant SG, et al. Comparative efficacy of olmesartan, losartan, valsartan, and irbesartan in the control of essential hypertension. J Clin Hypertens. 2001;3(5):283–291. Olmesartan medoxomil (Benecar) represents the seventh ARB to be introduced for the treatment of hypertension. A pro-drug, it is rapidly and completely deesterified in the gut to its active metabolite, olmesartan. It is a once-a-day antihypertensive agent with a side-effect profile similar to placebo with no significant drug-to-drug interactions. It has no requirement for dosage adjustment in those with renal insufficiency or mild-to-moderate hepatic disease. Although there is no data on its effect on clinical outcome, how olmesartan compares as a blood-pressure lowering agent at its starting dose to other ARBs already on the market was the subject of this study. The authors found that olmesartan was not only well tolerated, but, at its starting dose, was more effective in reducing cuff DBP than three of the more popular ARBs already on the market. In addition, it was equivalent to irbesartan, but more effective in reducing 24-hour ambulatory SBP than losartan and valsartan. As almost all of the patients in the study were white, we are not told of the drug's blood-pressure lowering ability in the 14% of the patients who were African American. In addition, the study did not evaluate how it will perform with the addition of a diuretic, well known to augment the blood pressure reduction achieved with ARB therapy, especially in the African American patient. ARBs have been recommended as first-line therapy in hypertensive type 2 diabetics with proteinuria or clinical nephropathy by the American Diabetes Association (Diabetes Care. 2002;25(suppl 1): S85–S89). Studies already in progress are evaluating the benefit of ARB therapy in those with left ventricular hypertrophy, post myocardial infarction, as well as in diastolic heart failure. Although this study suggests that there is a greater effect on DBP with initial doses of olmesartan, the impact of this finding on cardiovascular end points in a treatment algorithm that usually requires higher doses of each individual agent or additional agents to get to goal blood pressure remains unclear. Although ARBs May differ in their duration of action, degree of receptor binding, degree of blockade of the sympathetic nervous system, and cost, there appears to be more similarity in the seven agents that make up the ARB class than differences to suggest one is clearly superior over the others. We anxiously await comparative data on long-term outcomes as they become available. Hypertension, defined as a blood pressure at or above 140/90 mm Hg, is associated with an increased risk for cardiovascular (CV) disease. Multiple evidence-based trials have proven that with effective control of blood pressure, the risk for CV disease is lessened. Although insurance actuaries have recognized that CV risk increases at levels below those considered to be hypertensive, clinical information in this area is limited. To investigate the relationship between baseline blood pressure and the incidence of CV disease, researchers from the Framingham Heart Study studied 6859 middle-aged men and women (mean age, 50) with varying levels of blood pressure and no known CV disease at baseline from the original Framingham Heart and Offspring Study. A quarter of the group had high-normal blood pressure (SBP 130–139 mm Hg or a DBP of 85–89 mm Hg), a third had normal blood pressure (SBP of 120–129 mm Hg or a DBP of 80–84 mm Hg) and the rest had an optimal blood pressure (<120/80 mm Hg). The primary outcome measures, during a mean follow-up of 11 years, were time to occurrence of myocardial infarction, stroke, congestive heart failure (CHF), or death resulting from CV disease. Excluding all those with hypertension (blood pressure >139/89 mm Hg) or on antihypertensive medication, they found the higher the blood pressure, in men and women, the greater the risk of suffering a myocardial infarction, stroke, or CHF. The age-adjusted 10-year risk for CV disease by blood pressure status in females was 1.9% (optimal), 2.8% (normal), and 4.4% (high normal). For males it was 5.8% (optimal), 7.6% (normal), and 10.1% (high normal). Among those 35–64 years of age with high-normal blood pressure, the 10-year risk of developing CV disease was 4% in women and 8% in men. For those ages 65–90 years of age, the 10-year cumulative incidence of CV disease was 18% in women and 25% in men. Based on this observational study, in order to prevent a single heart attack, heart failure, or stroke, 28 men and 41 women with high-normal blood pressure would need to be treated for 5 years. The study suggests that high-normal blood pressure increases the risk for CV disease in a manner more similar to those with hypertension than normal blood pressure. The best form of therapy, if any, for this group at increased risk is unclear.—Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. 2001;345(18);1291–1207. Currently, 47% of the adult US population has an optimal blood pressure (<120/80 mm Hg) with another 21% having normal blood pressure (<130/85 mm Hg). The finding from this study that high-normal blood pressure (130–139/85–89 mm Hg) is associated with an increased risk for CV disease is an important observation like so many that the Framingham Heart Study has brought us over the years and has tremendous implications for the 13% of the US adult population, or roughly 20 million Americans, who have high-normal blood pressure. Although they often go untreated, current recommendations in the Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) calls for lifestyle modification in those with high-normal blood pressure and no other evidence of underlying vascular disease. Weight reduction, physical activity, moderation of alcohol intake, reduction in sodium intake, and a diet high in potassium, calcium, and magnesium are all recommended. Although these individuals often go untreated, eating a diet high in fruits, vegetables and grains as well as one low in salt and saturated fats as in the Dietary Approaches to Stop Hypertension (DASH) Trial is an evidence-based strategy that results in a significant reduction in blood pressure and promotes healthy cholesterol levels. It is of importance in the present study that the very subjects with high-normal blood pressure were older, heavier, and had higher cholesterol levels than those with optimal blood pressure and would seem to benefit the most from this strategy. Although these results are based on a single blood pressure measurement with all of its inherent variability, maintaining an optimal blood pressure (<120/80 mm Hg) appears to be ideal. Until the results of the Trial of Preventing Hypertension (TROPHY) study in those with high-normal blood pressure shows whether drug treatment is beneficial, the threshold for drug therapy in those with uncomplicated hypertension will remain at 140/90 mm Hg. Current guidelines will continue to recommend diet and exercise to lower high-normal blood pressure even though it more closely approximates the risk of hypertension than does optimal blood pressure. Microalbuminuria is an independent risk factor for stroke, myocardial infarction, congestive heart failure (CHF), and death in those with diabetes and appears to increase risk in those with hypertension as well. At present, however, its detection is recommended as a screening test only in those with diabetes. Furthermore, it is unclear whether individuals with albumin excretion rates below the threshold for microalbuminuria (30–300 mg/24 hr) are also at increased risk for cardiovascular 1(CV) events. To examine the relationship between baseline levels of albuminuria and future CV events, 9043 patients who were part of the Heart Outcomes Prevention Evaluation (HOPE) trial were randomized to either 10 mg of ramipril or placebo, and followed for the development of myocardial infarction, stroke, CV death, or total mortality. As in the original study, they were at least 55 years of age on entry with a history of CV disease (either coronary artery disease, stroke, or peripheral vascular disease) or a history of diabetes mellitus with one or more CV risk factors (n=3498). None of the patients had dipstick-positive proteinuria or established nephropathy on entry. Followed for a median of 4.5 years, subjects had a first morning urine collected at baseline, at 1 year, and at study end. Expressed as the albumin/creatinine ratio, microalbuminuria was defined as an albumin/creatinine ratio of 2 mg/mmol or more for both men and women. Assessed every 6 months, the primary aggregate end point of the study was myocardial infarction, stroke, CV death, or total mortality with hospitalization for CHF, a secondary end point. Microalbuminuria was detected in 33% of those with diabetes mellitus and 15% of patients without diabetes mellitus. Using Cox regression analysis with all variables entered into a multivariate model, participants were categorized by decile levels of microalbuminuria. Beginning below the cut-point for microalbuminuria, and seen both in those on placebo as well as ramipril, and in those both with and without diabetes, any degree of albuminuria increased the risk for major CV events, all-cause mortality, and hospitalization for CHF after adjustment for other CV risk factors. The authors conclude that in high-risk patients both with and without diabetes, any degree of albuminuria increases the risk for major CV events without a threshold effect.—Gerstein H, Mann J, Yi Q, et al., for the HOPE Study Investigators. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001;286:421–426. Microalbuminuria has been associated with diabetes, hypertension, smoking, hyperlipidemia, hyperhomocystinuria, and high intake of dietary protein. It has been unclear whether the presence of microalbuminuria is causal for CV disease or simply a marker of generalized endothelial disease. This study, based on one baseline measurement of albumin excretion, with all of its variability, and two more measurements during the study, suggests that increasing levels of albuminuria increasingly predict the risk for CV disease with no threshold that ceases to define risk. It is of interest that at present, other than in the diabetic, there is no recommendation that we screen patients for the presence of microalbuminuria. Perhaps this is because we remain unsure if microalbumin is a risk factor or a marker for generalized atherosclerotic disease. As all antihypertensive classes have been shown to lower albumin excretion with effective blood pressure reduction, before we recommend screening all high-risk patients with or without hypertension for its presence, we need to evaluate whether a specific intervention that reduces its occurrence also lessens CV risk. Until then, clinicians should concentrate on treating the proven CV risk factors that we so often fail to improve upon. Quantification of urinary albumin May soon be ready for prime time in all of our patients, not only as currently performed in those with diabetes, but also in those with underlying vascular disease with or without hypertension, who remain at high risk.