Treating Hypertension WITH ACE INHIBITORS.
This prospective, open-label, randomized study compared the outcomes in hypertensive subjects 65 to 84 years of age who received therapy with angiotensin-converting–enzyme (ACE) inhibitors or diuretic agents. The rate of cardiovascular events or death from any cause was lower among male subjects who received ACE inhibitors.
Treating hypertension in older persons with an ACE inhibitor may confer an advantage over a diuretic in terms of outcome, despite similar reductions of blood pressure. The difference may be particularly evident among men.
Related Editorial
Not infrequently, on release of the results of major multicenter trials, the lay press promulgates an immediate response before physicians have had time to assess the peer-reviewed paper. By the next morning, physicians are greeted by a multitude of messages containing frantic questions from patients about how the reported results relate to their particular problems. When the report deals with a common disease (such as hypertension), the magnitude of the public's anxieties is intensified. Moreover, when results appear to conflict with those of a previous study, not infrequently described as "landmark," there is potential for mass confusion and loss of confidence in individual health care providers, exacerbated by media reports that pose this rhetorical question: "Just what are we to believe?"
In this issue of the Journal, Wing et al.1 report the results of a major trial comparing the effects of angiotensin-converting–enzyme (ACE) inhibitors with the effects of diuretics on the rate of cardiovascular events in elderly hypertensive patients. The investigation, the Second Australian National Blood Pressure Study (ANBP2), involved 6083 patients who were followed by 1594 family practitioners for a median of 4.1 years. Numbers of patients and the design and conduct of the study appear reliable, but some of the results contradict those of another major trial, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).2 ALLHAT was designed to compare the diuretic chlorthalidone with agents representing each of three other classes of antihypertensive drugs (ACE inhibitors, calcium antagonists, and alpha-adrenergic–receptor inhibitors) and involved more than 42,000 patients from the United States and Canada. The trials should therefore be comparable. But ANBP2 indicates that ACE inhibitors have an outcome advantage over diuretics (particularly among older men), whereas ALLHAT concluded that diuretics were more effective for blood-pressure control, as well as in terms of outcomes. So what are we to believe?
First, we should consider the sources. Both trials were sponsored and supervised by national health research institutions with academic participation and without commercial influence. A second issue might be whether the drugs studied in each class were equivalent. The honest answer is that we do not really know. ANBP2 used hydrochlorothiazide as the diuretic, whereas ALLHAT used chlorthalidone. Hydrochlorothiazide has an excellent track record and was used as the diuretic in most early trials of antihypertensive therapy; chlorthalidone is equally well accepted. However, there have been no head-to-head trials comparing the efficacy of and outcomes with these two diuretics. In addition, ANBP2 used enalapril as the ACE inhibitor, whereas ALLHAT used lisinopril. Again, questions may be raised, since it is possible that one agent may have a greater effect not only on blood pressure, but also on local renin–angiotensin systems that may affect disease outcomes.3 There have not been (nor are there likely to be) head-to-head comparisons of the long-term efficacy of and outcomes with the two ACE inhibitors. We may also ask whether these were the only drugs used to control blood pressure in these trials. The answer to this question is equivocal. In both trials, other antihypertensive medications were frequently required to achieve blood-pressure goals, and the use of these additional agents also compounds the complexities of any comparison between the trials.
All of these are straightforward questions whose answers could explain the differences between the conclusions. There are also some more complex questions. Which agent controlled blood pressure better? The ANBP2 report indicates that there were similar reductions in blood pressure in the two treatment groups, whereas in ALLHAT, the diuretic-based regimen was more efficacious (as indicated both by the blood pressures and by the percentage of patients in whom the blood-pressure goal was achieved). We may well ask why there was a difference in blood pressure if the participating physicians were allowed to achieve the goal with the addition of the other classes of antihypertensive drugs.
What about clinical outcomes? Again, we must equivocate, because the trials used vastly different definitions of primary and secondary outcomes. The primary outcome in ANBP2 was the total number of fatal and nonfatal cardiovascular events, which favored enalapril. In ALLHAT, the treatment groups were similar in terms of the primary outcome of death from coronary causes or nonfatal myocardial infarction, but when combined with the secondary cardiovascular events, outcomes favored chlorthalidone. Perhaps comparison of the demographic and clinical characteristics of the subjects in the two trials can help. Age, sex, and body-mass index were similar. Ninety-five percent of the subjects in ANBP2 were white, whereas 35 percent of the subjects in ALLHAT were black. In ANBP2, the pretreatment blood pressures were higher. Could the differential in achieved blood pressure between the chlorthalidone group and the lisinopril group in ALLHAT have affected its results? The percentages of patients with diabetes, smokers, and patients with coronary heart disease or cerebrovascular disease in ANBP2 were lower. These characteristics could also have an effect on outcomes.4,5
In order to obtain firm answers to these questions for ourselves and our patients, medical leaders and responsible health care providers should assume more direct oversight of the interpretation of such studies. Whereas epidemiologists focus on responses at the population level in order to develop therapeutic guidelines, health care providers must deal with the specific relationship between the physician and the patient. This relationship is where the therapeutic tire meets the road, and there is no place for absolute or categorical answers. Population-based studies of therapies help to point the way but are not analogous to the care of individual patients.
Elsewhere in this issue of the Journal, there is an informative article by August6 that describes an exceedingly common clinical problem faced by all primary care physicians: the initial treatment of patients with less severe essential hypertension. Although such hypertension was formerly considered to be "mild," we must recognize that all hypertension is severe in that it is associated with an increased risk of premature illness and death. August outlines the importance of a comprehensive evaluation and the necessity for prompt recognition and treatment of hypertension.
Now we can develop specific resolutions to the apparent dilemma presented by the results of ANBP2 and ALLHAT. For patients with essential hypertension but without complications, it makes sense for the prescribing physician to choose a diuretic in a dose that does not cause potassium wasting, precipitate gout, or have other unwanted effects. In ANBP2 and ALLHAT, it was frequently necessary to prescribe a second or third medication in order to control blood pressure. In such a circumstance, the addition of an ACE inhibitor makes sense. Furthermore, a diuretic alone is not sufficient for the achievement of blood-pressure goals in some patients with hypertension, and both ACE inhibitors and diuretics are valuable and currently available as generic compounds. One should not lose sight of the fact that both diuretics and ACE inhibitors are extremely effective in improving clinical outcomes.7,8,9 However, patients with hypertension — particularly elderly patients — frequently have associated coexisting conditions. If a patient has diabetes, it would certainly be wise to initiate therapy with an ACE inhibitor, as long-term studies have clearly demonstrated.10,11,12 If a patient has cardiac failure, one might use both a diuretic and an ACE inhibitor. If there is a history of myocardial infarction, an ACE inhibitor diminishes the risks of future cardiac failure, a second infarction, and subsequent death13,14,15; a beta-blocker is also indicated for such a patient.7 If the patient has angina pectoris, whether from atherosclerotic epicardial coronary artery disease or from hypertensive arteriolar disease, it may also be wise to use a calcium antagonist. Dihydropyridine calcium antagonists not only relieve chest pain, but also help to prevent strokes.7,16
The answer to our question about what we are to believe has now become apparent. First, measure blood pressure in all patients. Second, if blood pressure remains elevated, control it with medication so as to achieve the blood-pressure goal (systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg). In selecting appropriate therapy, choose a drug or a combination of drugs for which there is strong evidence of effectiveness in persons with the type of problem found in the patient.
Finally, we must not join the clamor of media and industry, allowing newscasts to declare immediately which class of drugs is best. Treatment of the individual patient with hypertension is complicated, requiring time and judgment. In choosing between a diuretic and an ACE inhibitor, the physician can make a reasonable selection by reviewing the patient's history and course. We must remember that trials describe population averages for the purposes of developing guidelines, whereas physicians must focus on the individual patient's clinical responses.
Ibuprofen Could Be Bad for Heart Patients
Fri Feb 14, 7:31 AM ET By EMMA ROSS, AP Medical Writer
LONDON - Fresh evidence adds to suspicions that ibuprofen could be dangerous for most heart patients because it can block the blood-thinning benefits of aspirin.
New research published this week in The Lancet medical journal found that those taking both aspirin and ibuprofen were twice as likely to die during the study period as those who were taking aspirin alone or with other types of common pain relievers.
Scientists believe ibuprofen clogs a channel inside a clotting protein that aspirin acts on. Aspirin gets stuck behind the ibuprofen and cannot get to where it is supposed to go to thin the blood.
Aspirin is considered the most important medicine for heart disease. Nearly all heart patients take it every day because it prevents the clots that cause heart attacks and strokes. Ibuprofen, which is in Motrin and Advil among other brands, is widely used for arthritis and other aches and pains.
Scientists at the Medicines Monitoring Unit of Britain's Medical Research Council checked the medical records of 7,107 heart patients who had been discharged from hospitals between 1989 and 1997 with aspirin prescriptions and had survived at least one month after leaving the hospital.
They were divided into four groups according to their prescriptions.
The first group included those on aspirin alone.
The second were given aspirin and ibuprofen and the third group had aspirin with another pain killer, diclofenac. Ibuprofen and diclofenac both belong to a widely used class of pain relievers known as nonsteroidal anti-inflammatory drugs, or NSAIDs.
The last group included those taking aspirin with any other NSAID, such as acetaminophen, which is in Tylenol.
The researchers found that those taking ibuprofen were almost twice as likely as those taking aspirin alone to die by 1997. That meant that for every 1,000 patients treated, there were 12 extra deaths a year when ibuprofen was taken with aspirin.
For heart-related deaths, ibuprofen was linked to three extra deaths per 1,000 patients treated per year.
Experts say it is important to track both heart-related deaths and deaths in general because deaths are sometimes attributed to the wrong cause and heart-related cases may be missed. For instance, a death certificate may say the person died in a car crash when, in fact, a heart attack or stroke at the wheel caused the crash.
No extra deaths were seen in the groups taking the other types of NSAIDs.
"The message here is beginning to be 'go for something other than ibuprofen,'" said Garret FitzGerald, who was not connected with the latest study, but whose research sparked concerns about the combination just over a year ago.
"Mechanistically, you have a very clear rationale for why it should happen," said FitzGerald, professor of cardiovascular medicine and chair of pharmacology at the University of Pennsylvania. "Now we have four studies each coming out with the same message. It's several pieces of ancillary evidence that when assembled are more persuasive than when taken in isolation."
"Lots of people take these two kinds of drugs chronically and probably a large number take both together chronically," FitzGerald said. "Talk to your doctor before you embark on this combination thinking that it's totally innocuous because both are available over the counter."
Dr. Tom MacDonald, who led the Lancet study, said taking the odd ibuprofen for a few days would not be a problem. It's regular use that seems to be at issue.
But the findings are not rock solid, experts said.
"This definitely raises a red flag ... but I don't think this can be viewed as the definitive answer on the question," said Dr. Veronique Roger, head of cardiovascular research at the Mayo Clinic in Rochester, Minn., who was not connected to the study.
It could be that heart patients who take ibuprofen have additional conditions that in turn make them more prone to premature death and were not accounted for in the study, she noted.