Lifestyle Changes, Calcium Antagonists, Genes, and More
Introduction
In April, the results of 2 very different trials in hypertension were published in JAMA. One, PREMIER, was a government-supported study of the effects of lifestyle changes. The other was a trial comparing a long-acting calcium channel blocker (CCB) with standard therapy (beta-blocker or diuretic) in patients with hypertension and at least 1 additional risk for cardiovascular disease. This latter trial, CONVINCE, received wide media attention because it was published despite having been terminated early by the sponsor. Other hypertension news in this report includes new results with the first, and to date only, aldosterone antagonist approved for hypertension, eplerenone. Hypertension news also comes from several recent conferences: the Federation of American Societies for Experimental Biology (FASEB) meeting, "Experimental Biology 2003 - Translating the Genome" (grape news in hypertension), and the XV Scientific Meeting of the Inter-American Society of Hypertension (an analysis of blood pressure control in Hispanics in the ALLHAT data).
Multiple Lifestyle Changes Lower Blood Pressure in PREMIER
Multiple lifestyle changes can be implemented simultaneously to prevent or control high blood pressure and reduce cardiovascular risk, according to the main results of the PREMIER study, published in the April 23 issue of JAMA.[1] Supported by the National Heart, Lung, and Blood Institute, PREMIER was a randomized trial that compared the effects of 2 multicomponent behavioral interventions on blood pressure in 810 adults (62% women, 34% African American) with above-optimal blood pressure, including stage 1 hypertension (120-159/80-95 mm Hg), who were not taking any antihypertensive medications.[2] At the start of the trial, 38% of participants were diagnosed as hypertensive, and most were overweight and sedentary. Participants were randomized to advice only (typically from a dietitian), an established intervention that implemented established recommendations, or to an established intervention plus implementation of the Dietary Approaches to Stop Hypertension (DASH) diet. The DASH diet stresses consumption of fruits and vegetables and low-fat dairy products, and reduced intake of saturated and total fat. It has been demonstrated to lower blood pressure in hypertensive and borderline hypertensive subjects, particularly when combined with sodium restriction.
At 6 months, patients in both interventional groups had significantly reduced weight, improved fitness, and lowered sodium intake. After subtracting the change in the advice-only group, significant (P < .001) mean net reductions in SBP were seen in the "established" group (-3.7 mm Hg) and "established plus DASH" group (-4.3 mm Hg). The prevalence of hypertension was 26% in the advice-only group compared with only 17% in the established group and 12% in the established plus DASH group. Optimal blood pressure (< 120/< 80 mm Hg) was achieved in 30% of the established group and 35% of the established plus DASH group compared with only 19% of the advice only group.
Both the PREMIER investigators, and Thomas G. Pickering, MD, DPhil (Mount Sinai Medical Center, New York, NY) in an accompanying editorial,[5] noted that the net change in blood pressure, particularly with the addition of the DASH diet, was less than expected. Dr. Pickering pointed out that the participants were not following the DASH diet as closely as in earlier DASH studies and also suggested that the beneficial effects of the interventions may have been masked by the effects in the control, ie, advice-only, group. He also supported the authors' suggestion that the combination of 2 or more interventions may be less than the sum of the effects of the interventions individually, possibly because they act like antihypertensive drugs, where doubling the dose often produces only a small further decrement of blood pressure. Dr. Pickering also noted that the interventions used in PREMIER may not necessarily be less expensive or have fewer adverse effects than drug treatment. He recommends counseling as used in the advice-only group and recommended in the Sixth Report of the US Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI)[6] followed by weight loss advice for the obese and adoption of the DASH diet in normal-weight individuals.
CONVINCE Trial Results Published, Despite Premature Termination
The results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial, which were first presented last year at the annual meeting of the American Society of Hypertension, have now been published in JAMA,[7] an unprecedented move by the journal, since the trial was not completed. Although CONVINCE was planned with a mean follow-up of 5 years, it was terminated 2 years early by the sponsor "for commercial reasons," according to the investigators. CONVINCE was set up to assess the equivalence of therapy with controlled-onset extended-release (COER) verapamil and standard therapy (physician's choice of atenolol or hydrochlorothiazide) in preventing cardiovascular disease.[8] It was conducted at 661 centers in 15 countries. Between 1996 and 1998, 16,602 subjects diagnosed with hypertension and >/= 1 additional risk factor for cardiovascular disease were randomized to either COER verapamil 180 mg, or to atenolol 50 mg, or hydrochlorothiazide12.5 mg. Other antihypertensive drugs could be added according to a specific sequence, if needed.
After a mean follow-up of 3 years, CONVINCE was unable to demonstrate "equivalence" (statistically stronger than "noninferiority") of the COER verapamil-based regimen and a regimen starting with a beta-blocker or a diuretic. A total of 354 primary cardiovascular disease-related events occurred in the COER verapamil group vs 365 in the atenolol/hydrochlorothiazide group. All hazard ratios involving efficacy were close to 1.0, including the primary endpoint and the major cardiovascular disease endpoint and mortality. When considered in the context of other trials of CCBs, such as Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack trial (ALLHAT),[9] the CONVINCE data indicate that CCB therapy for reducing cardiovascular disease-related morbidity and mortality is similar to, but not better than, diuretic or beta-blocker therapy, the investigators conclude. Primary principal investigator of CONVINCE, Henry R. Black, MD (Rush Medical College of Rush University, Chicago, Illinois), has said that he believes that equivalence would have emerged if the trial had been completed. In a JAMA editorial,[10] Bruce M. Psaty, MD, PhD (University of Washington, Seattle) and Drummond Rennie, MD (University of California, San Francisco) speculate that if the trial had run to completion, the primary results might have shown verapamil to be slightly better than the beta-blocker and the diuretic better than verapamil. They are highly critical of the termination of the trial, saying that "the willful creation of an underpowered study by early stopping of CONVINCE seems unethical." While allowing that the sponsor "may have made the best and most ethical choice among a set of complex problems," they refer to the lack of detailed information about the reasons for the decision as an "unfortunate approach."
Eplerenone Superior to Losartan in Black Patients, Reduces Microalbuminuria in the Elderly According to a study published in the April 2 issue of Journal of the American College of Cardiology, the aldosterone antagonist, eplerenone, is significantly more effective than the angiotensin receptor blocker (ARB) losartan in reducing both DBP and SBP in black and white patients combined and in black patients as a predefined subset.[11] In the study, 551 patients (348 black and 203 white) with mild-to-moderate hypertension were randomized at centers in the United States and South Africa to treatment with eplerenone 50 mg, losartan 50, or placebo daily. After 16 weeks of monotherapy, mean decrements in SBP and DBP were significantly greater with eplerenone than with placebo or losartan in all patients combined and in black patients. Eplerenone was as effective as losartan in reducing SBP and DBP in high renin (ie, white) patients, but more effective then losartan in moderate and low renin (ie, mainly black) patients, suggesting that eplerenone may protect patients from hypertension-related target organ damage, investigators John M. Flack, MD (Wayne State University, Detroit, Michigan) and colleagues suggest. Other patient populations that responded consistently to eplerenone included men, women, obese patients, nonobese patients, and patients with SBP >/= 160 mm Hg, which may contribute to higher treatment success with eplerenone (treatment failure was only 11.0% with eplerenone vs 24.9% and 22.9% with placebo and losartan, respectively). Both agents had a good tolerability profile.
In an accompanying editorial comment,[12] Ori Ben-Yahouda, MD (University of California, San Diego) notes that ARBs are known to be relatively ineffective as monotherapy in black patients. Welcoming the news of more efficacious treatments of hypertension, particularly in black patients, he nevertheless cautions that the use of racial designations in clinical studies is an imprecise and problematic surrogate for genetic polymorphisms as well as the social, economic, and other factors that influence biology. There is a risk, particularly in the genetically very heterogeneous US population, of assuming a certain biologic effect simply on the basis of race, Dr. Ben-Yahouda maintains. Genetics, he believes, will provide the tools to tailor therapy in a racially blind manner, based on individual determinants.
Another study of eplerenone has shown that it is as effective as the CCB amlodipine in older hypertensive patients with systolic hypertension.[13] Twenty-four weeks after 269 patients aged >/- 50 years with widened pulse pressure hypertension were randomized to eplerenone 50-200 mg daily or amlodipine 2.5 mg daily, eplerenone and amlodipine had produced similar reductions in systolic and pulse pressure and improved arterial elasticity. Eplerenone reduced microalbuminuria to a greater extent than amlodipine. Reductions in clinic DBP were modestly larger on amlodipine. Both antihypertensive agents had similar tolerability.
"Grape Expectations" in Hypertension
More news about potential grape-related treatments for hypertension comes from the FASEB meeting held in San Diego, California, April 11-15. In a double-blind, randomized study in 80 men aged 45-70 years with chronic erectile dysfunction, men with high baseline SBP (> 132 mm Hg) showed improvements in both SBP and DBP after drinking Concord grape juice for 12 weeks.[14] SBP fell from average baseline 142.7 mm Hg to 137.0 mm Hg and DBP from 87.9 to 82.1 mm Hg. Men with high baseline SBP who drank a control drink, an isotonic beverage, showed no change in blood pressure from baseline. Both groups ingested an average of 12 ounces of drink per day. The study was funded by Welch Foods Inc, the US manufacturer of grape-based foods.
Another US study presented at the FASEB meeting has shown that a diet moderately high (0.5%) in grape seed extract reduced salt-sensitive hypertension in young estrogen-depleted spontaneously hypertensive rats.[15] The effect of adding grape seed to the diet had the same effect as addition of phytoestrogens. The addition of grape seed extract or phytoestrogens did not affect heart rate or body weight in the rats, suggesting similar mechanisms on blood pressure in these animals. The researchers suggest that mechanisms other than estrogen receptor activation may underlie the beneficial effects of estrogen therapy and that, as a result, grape seed extract could be a useful supplement to blunt hypertension in postmenopausal women.
Blood Pressure Control in ALLHAT Higher in Hispanics Than in Blacks or Whites
Although blood pressure control (< 140/90 mm Hg) rates among Hispanics in North America are lower than those of non-Hispanic whites and much lower than desired, data from the ALLHAT presented at the XV Scientific Meeting of the Inter-American Society of Hypertension, held April 27-30, in San Antonio, Texas, show that blood pressure can be controlled in most Hispanics with diverse practice settings using available medications.[16] In ALLHAT, hypertensive patients with at least 1 other CHD risk factor were randomly allocated to 1 of 3 blinded study drugs: chlorthalidone 12.5-25.0 mg/day, amlodipine 2.5-10.0 mg/day, or lisinopril 10-40 mg/day. Doses were increased and drugs from other classes were added as needed to achieve blood pressure < 140/90 mm Hg. A total of 6329 Hispanics were included in the 33,357-patient population of ALLHAT, of whom 15.7% were white Hispanics and 3.3% black Hispanics. At baseline, blood pressure was controlled in 21% of black Hispanics and 23% of white Hispanics, but after 3 years of therapy, 68% and 71%, respectively, had controlled blood pressure. This compared with 57% and 65% of black and white non-Hispanics, respectively. At 3 years, DBP < 90 mm Hg was similar in the 4 groups, but SBP < 140 mm Hg was 6% to 10% higher for Hispanics. Among Hispanics, 49% needed >/= 2 drugs to achieve normal blood pressure whereas 79% of non-Hispanics needed >/= 2 drugs.
Ramipril May Be Better Than Other ACE Inhibitors After Acute MI
By Will Boggs, MD
Ramipril provides better outcomes for unselected patients after an acute myocardial infarction than do other angiotensin converting-enzyme (ACE) inhibitors, according to a report in the November 15th American Journal of Cardiology.
Ramipril has been shown to reduce the risk of acute MI in patients with atherosclerosis, the authors explain, and ACE inhibitors have been shown in recent trials to lower mortality after acute MI.
Dr. Harm Wienbergen from Herzzentrum Ludwigshafen in Ludwigshafen, Germany and colleagues analyzed outcomes in 14,608 consecutive patients; l4.7% received ramipril and 39.0% received other ACE inhibitors. The remaining subjects were not treated with an ACE inhibitor. All of the subjects, who were enrolled in the Maximal Individual Therapy of Acute Myocardial Infarction PLUS registry (MITRA PLUS), had ST-elevation acute MI and presented to 217 German hospitals.
Hospital mortality in ramipril-treated patients was only 5.8%, the authors report, significantly lower than that in other ACE inhibitor-treated patients (8.9%) and less than half that in acute MI patients that received no ACE inhibitor (12.3%).
Ramipril-treated patients also had significantly lower rates of nonfatal major adverse coronary and cerebrovascular events than did other ACE inhibitor-treated patients or patients untreated with ACE inhibitors, the report indicates. The superiority of ramipril treatment held for patients with anterior MI and for those with inferior MI, the researchers note.
The rate of heart failure at discharge was lower for ramipril-treated patients than for patients who received no ACE inhibitor, the results indicate, but the heart failure rate was not significantly better than that of other ACE inhibitor-treated patients.
"Studies shows that ACE inhibitor treatment is associated with a better clinical outcome than no ACE inhibitor treatment after AMI," Dr. Wienbergen told Reuters Health. "In addition to this 'class effect' of ACE inhibitors, patients with ramipril therapy showed the best clinical outcome of the analyzed patients."
"We could not analyze differences between the treatment doses of the ACE inhibitors in our registry," Dr. Wienbergen added. "This would be an interesting additional analysis of future registry studies to evaluate the benefit of ramipril compared to other ACE inhibitors in clinical practice."
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