Introduction
Cardiology news at the end of 2002 was dominated by the announcement of the results of the largest clinical trial ever undertaken in hypertension, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).[1,2] This combined trial of blood pressure and cholesterol lowering was conceived in an era when angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs) were relatively new classes of drugs, and before publication of the results of the first major trial with a statin, the Scandinavian Simvastatin Survival Study (4S).[3] Since ALLHAT was started in 1994, other major studies have been conducted with all these classes of drugs and newer types of antihypertensive treatments have emerged. Statins have become part of "usual care" in the treatment of hypercholesterolemia. In this context, the results of the ALLHAT blood pressure study, reported below, were a surprise to many, and the debate surrounding them will no doubt continue well into 2003, if not longer.
Other hypertension research reported at the end of 2002 and the start of 2003 was, in some ways, no less controversial. New findings were announced that strengthen the link of "normal type" blood pressure with vascular mortality; the possibility of a cheap preventive treatment for high blood pressure in young smokers was raised; and, most recently, Spanish researchers have cast doubt on the validity of claims made in many advertisements for antihypertensive drugs published in their national medical journals.
The major results of the ALLHAT blood pressure study, announced in Washington on December 17th and published simultaneously in JAMA[1,2] indicated that less expensive, traditional thiazide-type diuretics are more effective than some newer medications, including ACE inhibitors and CCBs, for the treatment of hypertension and the prevention of some forms of heart disease. Consequently, the ALLHAT investigators concluded that for most patients diagnosed with hypertension, treatment should begin with a thiazide-type diuretic.
ALLHAT was carried out between February 1994 and March 2002. A total of 42,418 high-risk hypertensive patients aged ≥ 55 years were enrolled at 623 centers in Canada, Puerto Rico, the United States, and the US Virgin Islands. To be enrolled in ALLHAT, patients had to have systolic blood pressure (SBP) ≥ 140 mm Hg and/or diastolic blood pressure (DBP) ≥ 90 mm Hg or be taking antihypertensive medication, and have at least 1 other risk factor for coronary heart disease (CHD), including cigarette smoking or type 2 diabetes. All participants underwent medical checkups at 3, 6, 9, and 12 months after entry into the study and every 4 months thereafter.
Patients were randomized in a double-blind manner to receive 1 of 4 antihypertensive agents: a thiazide-type diuretic, chlorthalidone; an ACE inhibitor, lisinopril; a CCB, amlodipine; or an alpha-adrenergic blocker, doxazosin. At the discretion of the patients' physicians, doses of the study drugs were optimized and then additional drugs from other classes (atenolol, clonidine, or reserpine) were prescribed as needed to achieve blood pressure control. The primary outcome of the study was fatal CHD or nonfatal myocardial infarction (MI) combined. Secondary outcomes included all-cause mortality, stroke, combined CHD, and combined cardiovascular disease.
The doxazosin arm of ALLHAT was stopped in March 2000 because of a 25% higher rate of combined cardiovascular events and a 2-fold higher rate of heart failure compared with chlorthalidone.[4] The remaining 33,357 patients stayed on their study drugs through the end of the study. Of this population, 15,255 were randomized to chlorthalidone (12.5-25.0 mg/day), 9048 to amlodipine (2.5-10.0 mg/day), and 9054 to lisinopril (10-40 mg/day).
After an average 5 years of follow-up, there were no significant differences in the primary outcome (fatal CHD or nonfatal MI) among the 3 treatment groups. However, there were differences in secondary outcomes for both of the newer drugs compared with the diuretic. Mean 5-year SBP levels were significantly higher in the amlodipine group (0.8 mm Hg, P = .03) and the lisinopril group (2 mm Hg, P < .001) compared with chlorthalidone, although 5-year DBP levels were significantly lower with amlodipine (0.8 mm Hg, P < .001).
Secondary outcomes were similar for amlodipine and chlorthalidone, except for a higher 6-year rate of heart failure with amlodipine (10.3% vs 7.7%). Compared with chlorthalidone, lisinopril was associated with higher 6-year rates of combined cardiovascular disease (33.3% vs 30.9%, P < .001), stroke (6.3% vs 5.6%, P = .01), and heart failure (8.7% vs 7.7%, P < .001). Significant differences were seen in black patients on lisinopril vs chlorthalidone, with a 4 mm Hg higher mean SBP compared with 2 mm Hg higher in nonblacks, a 40% higher rate of stroke compared with no difference in nonblacks, and a 19% higher rate of combined cardiovascular disease compared with 6% higher in nonblacks.
No significant differences were found in the incidence of cancer, mortality, hospitalization, or gastrointestinal bleeding among the treatment groups. More cases (n = 38) of angioedema occurred in patients on lisinopril, 1 of whom consequently died. Patients on chlorthalidone had more hypokalemia, higher mean serum cholesterol and glucose levels, and a slightly higher incidence of new cases of diabetes at 4-year follow-up. Creatinine base measures of renal function were more favorable in the amlodipine group overall and in some cases in the lisinopril group, but rates of end-stage renal disease did not differ among the treatment groups.
The ALLHAT investigators recommend that their results should be widely applied in patient care. According to the trial leaders, drug treatment for hypertension should begin with a thiazide-type diuretic. In addition to the perceived superiority of diuretics, the ALLHAT investigators also praised the lower cost of these drugs. They point out that between 1982 and 1992, diuretic use fell from 56% to 27% of antihypertensive prescriptions, and that had this decrease not occurred, antihypertensive drug costs for that period would have been about $3.1 billion less.
For those few patients who cannot tolerate a diuretic, a beta-blocker, an ACE inhibitor, or a CCB -- but not an alpha-blocker -- can then be used to start treatment. The investigators also acknowledge that most patients will need more than 1 drug to adequately control their blood pressure (63% of patients in ALLHAT were on ≥ 2 drugs by the end of the study), but insist that 1 of the drugs used should almost always be a diuretic. Patients currently on an antihypertensive drug other than a diuretic should not stop taking their medication, but they should talk with their physician about adding or switching to a diuretic for their treatment.
ALLHAT was not designed to investigate which class of antihypertensive drug should be the preferred second-line treatment in any group of patients. (This is expected to be answered in 2003/2004 by the results of the Anglo-Scandinavian Cardiac Outcomes Trial [ASCOT], which is comparing the effects of a beta-blocker [atenolol] with/without a diuretic vs a CCB [amlodipine] with/without an ACE inhibitor in hypertensive patients.[5])
The announcement of the ALLHAT results has given rise to much debate, both within the medical community and in the media at large. Immediate reactions to the results are emerging, and more considered comments are beginning to be published online and in print. The ALLHAT investigators believe that their results "are consistent in large part with evidence from other clinical trials." They point out that many of the newer antihypertensive medications were approved on the basis of studies showing that they reduced blood pressure and the risk of heart disease compared with a placebo, and that that they were not tested against each other. They cite other active-controlled trials -- such as the second Swedish Trial in Old Patients with Hypertension (STOP-Hypertension 2)[6] and the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) trial,[7] in which thiazide-like diuretics and dihydropyridine CCBs were studied -- as reinforcing the findings of both similar rates of CHD and stroke in the amlodipine and chlorthalidone groups as well as the higher rate of heart failure with the CCB in ALLHAT.
The most surprising result of ALLHAT to most people, however, was the increased risk of heart failure associated with lisinopril, contrary to the findings of such landmark trials as Studies Of Left Ventricular Dysfunction (SOLVD)[8] and Heart Outcomes Prevention Evaluation (HOPE).[9] The ALLHAT investigators again point out that these were placebo-controlled trials, which must limit the relevance of their findings. Others, however, including Lawrence K. Appel, MD, MPH (Johns Hopkins University, Baltimore, Maryland), in his accompanying commentary on ALLHAT in JAMA,[10] find this result "difficult to reconcile with the well-documented benefits of ACE inhibitors in heart failure." Others have suggested that a higher dose of the ACE inhibitor, as well as using one that is hydrophobic, such as ramipril or quinapril, unlike the hydrophilic lisinopril, might have made a difference. Over the relatively quiet holiday period, however, most of these comments have been informal, and we await the more detailed comments and rebuttals, as well as results of the ALLHAT substudies, for further elucidation.
JNC-VII Guidelines scheduled for May 2003. Claude Lenfant, MD, Director of the National Heart, Lung, and Blood Institute (NHLBI), announced on December 18 the appointment of the committee to produce the seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, known as JNC-VII. The committee will be chaired by Aram Chobanian, MD, Dean of Boston University Medical School and Provost of Boston University Medical Center, Massachusetts. Dr. Chobanian was previously on the executive committees for JNC-VI and JNC-V. JNC-VI, made available by the NHLBI in 1997, recommends a diuretic or a beta-blocker for initial treatment of uncomplicated hypertension.[11]
JNC-VII is expected to incorporate findings from ALLHAT and other recent clinical trials. It is provisionally scheduled to be presented during the 18th Annual Meeting of the American Society of Hypertension, to be held in May 2003 in New York City.
On January 6th, the US FDA's Cardiovascular and Renal Drugs Advisory Committee announced its endorsement for expanding the approval of the angiotensin type-2 receptor blocker (ARB) losartan (Cozaar, Merck & Co) on the basis of data from the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, which showed a significant reduction in the risk of stroke in hypertensive patients with left ventricular hypertrophy (LVH).[12] The advisory committee's recommendation did not provide specific language for the new indication. The committee declined to support the use of losartan to reduce cardiovascular death, stroke, and MI in the same patients, which had also been submitted as part of the supplemental new drug application. The committee also called for an additional caution on the label, alerting physicians that black patients did not appear to benefit from losartan in the LIFE study.
Losartan was approved for marketing as an antihypertensive agent in the United States in 1995. If this additional indication is granted -- and the FDA usually follows the recommendations of its outside expert panels -- it will be the first ARB to be marketed with this indication.
Folic acid reduces blood pressure in smokers. UK researchers reported in the Journal of Internal Medicine[13] that short-term folic acid supplementation significantly enhances endothelial function and reduces blood pressure in young chronic smokers. In a randomized controlled trial carried out at Guy's, King's, and St Thomas' School of Medicine, London, 24 healthy cigarette smokers (mean age +/- SEM = 37.8 +/- 2.5 years) were randomly assigned to receive either folic acid 5 mg/day or placebo. After 4 weeks, the group on folic acid showed significant reductions in plasma concentrations of homocysteine, an independent risk marker for cardiovascular disease that induces endothelial dysfunction and arterial stiffness. Endothelium-dependent vasodilatation was significantly enhanced in the folic acid group, whereas endothelium-independent vasodilatation remained unaffected. Folic acid also induced significant reductions in SBP (121 +/- 3 to 113 +/- 2 mm Hg; P < .01), DBP (71 +/- 1 to 67 +/- 1 mm Hg; P < .01), and mean arterial blood pressure (88 +/- 2 to 83 +/- 1 mm Hg; P < .01). Carotid artery pulse wave velocity was unchanged. The effects on endothelial function and blood pressure were largely independent of the homocysteine-lowering effects. Arduino Mangoni, MD, and colleagues suggest from these results that such a simple, nontoxic, and cheap vitamin intervention might be useful in primary cardiovascular prevention in this high-risk group. They acknowledge, however, that the results of their small study, with its lack of "hard" endpoints such as cardiovascular morbidity and morbidity, need to be confirmed in large multicenter trials.
A meta-analysis of 1 million adults in 61 prospective observational studies of blood pressure and mortality has shown that at age 40-69 years, each difference of 20 mm Hg in "usual" SBP is associated with a > 2-fold increase in the rate of death from stroke and a 2-fold increase in death rates from ischemic heart disease and other vascular causes. The proportional differences in vascular mortality were about half as extreme at ages 80-89 years as at ages 40-49 years, but the annual absolute differences in risk were greater in the older ages. These findings, published in the December 14th issue of The Lancet,[14] indicate that blood pressure is even more strongly related to the risks of death from cardiovascular causes than was previously believed.
Sarah Lewington, DPhil, and colleagues from the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford, United Kingdom, combined data from trials carried out in Australia, China, Europe, Israel, Japan, and North America. During 12.7 million patient-years of follow-up, 120,000 deaths occurred involving 56,000 vascular deaths (12,000 stroke-related deaths, 24,000 deaths related to ischemic heart disease, and 10,000 due to other vascular causes) and 66,000 other (noncardiac) deaths at ages 40-89 years. The meta-analysis, which involved "time-dependent" correction for regression dilution, correlated mortality during each decade of age at death with the estimated usual blood pressure at the start of that decade. The researchers found that lower blood pressure was strongly related to lower risk of death from cardiovascular causes throughout the so-called "normal range," ie, down to SBP 115 mm Hg and DBP 75 mm Hg. This relationship was valid not only in middle age but also in the elderly. The age-specific associations were similar for men and women, and for patients with cerebral hemorrhage and cerebral ischemia.
Speaking at the time of publication of the Lancet report, Dr. Lewington noted that the results of this meta-analysis complement those of randomized trials, which have shown that blood pressure lowering can produce rapid reductions in vascular disease risk. Compared with randomized trials, which typically last only a few years, however, this meta-analysis showed that even greater differences in risk are likely to be produced by prolonged differences in blood pressure. For example, a 10 mm Hg lower usual SBP or 5 mm Hg lower usual DBP would, in the long term, be associated with about 40% lower risk of stroke death and about 30% lower risk of death from ischemic heart disease or other vascular causes throughout middle age.
Dr. Lewington pointed out that in the general population, producing persistent reductions in average blood pressure of just a few mm Hg by some widely practicable methods (such as reducing sodium intake in manufactured foods) should avoid large absolute numbers of premature deaths and disabling strokes, especially in places that, perhaps for other reasons, have relatively high stroke rates (such as Northern China) or high rates of ischemic heart disease (such as Eastern Europe).
Dr. Lewington and her colleagues recommend SBP, rather than DBP, measurement as the more informative predictor of risk, irrespective of age.
Physicians should be wary of claims made in pharmaceutical advertisements, even when they are supported by references to randomized clinical trials published in reputable medical journals, according to a report by Spanish researchers published in the January 4th issue of The Lancet.[15] Plar Villanueva, MD, and colleagues, in an independent study funded by the Fundacion Instituto de Investigacion en Servicios de Salud, Valencia, Spain, investigated advertisements for antihypertensive and lipid-lowering drugs in 6 Spanish medical journals in 1997. The journals included peer-reviewed and non-peer-reviewed journals, subscription and free journals, and represented a range of differently ranked journals. Two were official publications of the Spanish societies of family physicians and cardiologists. All were known to be widely read by general practitioners and cardiologists.
A total of 264 different advertisements for antihypertensives were identified, 32 with references, containing a total of 73 promotional claims with bibliographic references. In addition, 23 advertisements were identified for lipid-lowering drugs, 7 with references, containing 52 promotional claims with bibliographic references. The most frequently cited journals were Circulation (17.6% of references), The New England Journal of Medicine (14.4%), and The Lancet (8.8%).
The researchers found that 45 (44.1%) of the total 102 promotional claims were not supported by the bibliographic reference. This was more frequent for antihypertensive advertisements (68.6%) than for lipid-lowering drug advertisements (19.6%). Most of these nonsupported claims (44.4%) recommended the drug in a patient group different from the one studied in the trial cited. Another 15 claims were transferred from studies in high-risk groups to the general population. In 10 advertisements (21.3% of the nonsupported claims), the publicity exaggerated the results reported; in 9 (19.1%), false statements were made; and in 6 (12.8%), the work referenced had no relation to the promotional claim.
Dr. Villanueva and her colleagues suggest that one of the reasons for their findings is that the knowledge obtained from randomized clinical trials is becoming an important promotional strategy used by the pharmaceutical industry in "aggressive campaigns to change prescribers' habits." They suggest that although pharmaceutical publications are strictly regulated in Spain, as in the rest of Europe, the journals themselves need to commit to only "truthful" advertising but are reluctant to do so.
Medical journals worldwide are defended in an accompanying commentary in The Lancet by Robert H. Fletcher, MD, MSc (Harvard Medical School and Harvard Pilgrim Heath Care, Boston),[16] who points out that the editors do not have the resources to fully review all advertisements. He advises readers not to "take claims in journal adverts, with or without credible-appearing references, on face value." However, he also points out that readers should not accept the conclusions of original research uncritically, either. Allowing that government regulators and editors do try to improve the accuracy and content of both articles and advertisements, he nevertheless concludes that readers "must still take personal responsibility for judging the validity of assertions, especially those made in adverts."
Medscape Cardiology. 2003;7(1) © 2003 Medscape
Cite this: ALLHAT -- Results and Reactions -- Plus New Guidelines, New Approvals, and the Ethics of Journal Publishing - Medscape - Jan 14, 2003.
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