Diuretics for hypertension get a big boost, but will data change prescribing patterns?
By Jason van Steenburgh
The role of diuretics in treating hypertension received a major boost late last year.
For years, researchers and practice guidelines have urged physicians to give diuretics a bigger role in treating hypertension. Worried about side effects like hypokalemia and elevated cholesterol, however, many physicians have instead given diuretics the cold shoulder. Rather than using this old standard, many have prescribed newer angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs).
Results from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), however, may finally put to rest many physicians' fears about diuretics. While the long-awaited study did find that the drugs may alter certain biochemical markers, it showed that diuretics not only control blood pressure as well as other drugs, but also help prevent more strokes and congestive heart failure.
The results were so convincing that the ALLHAT researchers urged physicians to turn to diuretics first when treating newly diagnosed hypertension, and to switch patients with controlled blood pressure from ACE inhibitors and CCBs to diuretics. And if you're not going to switch you patients to diuretics, they said, you should at the very least consider adding diuretics to multiple drug regimens for hypertension.
The question now is whether physicians will change their ways. While the ALLHAT data were impressive, some physicians say they're not sure how to apply the new evidence to specific patients.
Some wonder which patients are not good candidates for diuretics and should receive ACE inhibitors and CCBs instead. And others wonder when they should switch patients taking other drugs to diuretics.
Biochemical effects of diuretics
Ask researchers why physicians are reluctant to prescribe diuretics, and many point to drug advertising. For years, drug companies have cited research showing that in many patients, diuretics boost cholesterol and blood sugar and lower potassium. At the same time, drug companies have aggressively marketed the beneficial effects of ACE inhibitors and CCBs.
The ALLHAT data confirm that diuretics can indeed affect these measures. Researchers found that chlorthalidone, the diuretic used in the study, slightly raised cholesterol and glucose levels and caused more hypokalemia than other antihypertensive agents. Researchers treated hypokalemia in about 8% of patients taking diuretics, compared to 4% of patients taking CCBs and 2% taking ACE inhibitors.
The ALLHAT investigators, however, pointed out that by focusing on these measures instead of on morbidity and mortality rates, physicians miss the big picture. The ALLHAT data, for example, found that patients taking CCBs experienced heart failure 38% more often than patients taking diuretics. Patients taking ACE inhibitors had a 15% higher risk of stroke and a 10% higher risk of combined cardiovascular disease than patients on diuretics.
Nevertheless, the ALLHAT data reinforce many physicians' prejudice against using diuretics. "I am biased against diuretics because I've dealt with a lot of hypokalemia-based arrhythmias," said Richard B. Whiting, FACP, chief of medicine and cardiology at St. Mary's Health Center in St. Louis and Governor for the College's Missouri Chapter. "Diuretics can work over years to be subtly arrhythmagenic."
Other physicians, however, say that new data show that the side effects of diuretics are not as serious as many physicians think. William C. Cushman, FACP, an ALLHAT researcher and chief of the preventive medicine section at the Veterans Affairs Medical Center in Memphis, said older trials that used higher doses of diuretics gave the drugs a reputation for causing hypokalemia that is no longer accurate. The lower doses used in the ALLHAT trials may still produce a hypokalemic effect, he said, but they reduce plasma potassium by only 0.3 milliequivalents/liter, not 1 to 1.5 milliequivalents/liter reported in earlier studies.
In diabetics, diuretics slightly increased insulin resistance compared to ACE inhibitors and CCBs. However, blood pressure control and the risk of adverse cardiovascular events for diabetics on diuretics were the same or better.
Because so many ALLHAT patients were taking statins to control their cholesterol, researchers had difficulty evaluating diuretics' effect on lipids. According to Marvin Moser, FACP, a clinical professor of medicine at Yale University in New Haven, Conn., past research had shown that the use of diuretics resulted in a slight difference in cholesterol levels when compared to other antihypertensive drugs.
The biochemical changes caused by diuretics pale in comparison to the drugs' ability to reduce morbidity and mortality.
Dr. Moser, however, who has been a prominent advocate of using diuretics as a preferred therapy for the long-term management of hypertension, noted that changes like increased levels of cholesterol usually last for less than a year. He also said that despite this finding, repeated studies have reported reduced incidence of heart failure, strokes and coronary events.
While the clinical significance of hypokalemia and slightly elevated insulin resistance may be up for debate, most hypertension experts say that the bottom line is clear: The biochemical changes caused by diuretics pale in comparison to the drugs' ability to reduce morbidity and mortality.
Diuretics vs. other drugs
Although ALLHAT initially gave patients a single drug, most eventually needed two or more additional drugs to control their blood pressure. Because diuretics were so effective and safe, the study's authors urged physicians to include diuretics in all multi-drug regimens to control hypertension.
Experts note that problems like a history of gout give a clear reason to avoid diuretics. Here are some instances in which researchers say physicians should consider starting patients on ACE inhibitors or CCBs:
ACE inhibitors. If you treat diabetics with advanced renal disease (creatinine grater than 2.5 milligrams per deciliter), you should probably choose an ACE inhibitor over a diuretic. Thiazide diuretics generally don't work with these patients, and ACE inhibitors may offer advantages that go beyond just treating hypertension.
William G. Kussmaul III, FACP, associate professor of medicine at Drexel University College of Medicine in Philadelphia, said that ACE inhibitors lower the risk of progression to kidney failure by as much as 25% and are effective in patients with microalbuminuria. "With the hypertension benefits, you can kill two birds with one stone," he said.
(For more information, see "Some surprising uses for ACE inhibitors.")
Dr. Moser, however, said that it is not clear that all of these benefits come exclusively from ACE inhibitors. He pointed out, for example, that the subjects in most of the studies that support ACE inhibitors also took a diuretic. It would appear, he added, that many of these patients needed both an ACE inhibitor and a diuretic to control their blood pressure and realize other important benefits.
Although ACE inhibitors seem to be the right choice for patients with moderate proteinuria and impaired kidney function, treating diabetics without renal disease is more controversial. ALLHAT researchers found that diuretics lowered blood pressure in these patients as well as ACE inhibitors. Because diabetics taking ACE inhibitors tend to have more strokes (particularly black Americans) and heart failure than those taking diuretics, some experts say that diuretics are ideal for controlling hypertension in early-stage diabetics.
Donald G. Vidt, FACP, a consultant to the department of nephrology and hypertension at the Cleveland Heart Clinic in Cleveland, said that newly diagnosed diabetics with some hypertension and no evidence of kidney disease are "tough calls. We have no data from major clinical trials that they benefit more from an ACE inhibitor in the long term."
Not everyone agrees. St. Mary's Dr. Whiting said he uses ACE inhibitors to protect against renal insufficiency even in patients with mild insulin resistance.
"They aren't diabetic yet, but they are going to get there," he explained. "Some data from small trials show ACE inhibitors can delay the onset of renal insufficiency or dialysis for many years."
Calcium channel blockers. Hypertensive patients with coronary spasm and angina pectoris have been and remain good candidates for CCBs. (Beta-blockers are also highly effective in these instances.)
Now that the ALLHAT results are in, however, many experts suggest adding a diuretic to these patients' therapies, especially if the CCB is not controlling the patient's blood pressure. Besides helping control blood pressure, they say, the diuretic will counterbalance the higher risk of heart failure with CCBs.
Making the switch
What about patients who are already taking ACE inhibitors and calcium channel blockers? Should you switch them to diuretics?
Many physicians say that barring obvious contraindications, the decision to switch depends on how well you're controlling the patient's blood pressure. Many swear by this conventional wisdom: Don't mess with success. A new drug could introduce side effects and lead patients to stop taking their medication.
While that old adage may have some truth, experts say ALLHAT showed that diuretics work. Dr. Cushman from the Memphis VA said that more than 60% of the ALLHAT subjects were already receiving nondiuretic antihypertensive therapy before being randomized to one of the three therapies in the trial. Before entering the trial, blood pressure was under control in only 30% of the patients. After ALLHAT, blood pressure was controlled in 66% of patients.
That has led some analysts to claim that if physicians aggressively pursued multi-drug therapies, an additional 2.5 million Americans could control their blood pressure.
Patients who take ACE inhibitors or CCBs for hypertension and have uncontrolled blood pressure are obvious candidates to switch to a diuretic.
And if you have patients who should not stop taking either medicine, consider adding a diuretic to their regimen. Dr. Vidt from the Cleveland Clinic said that studies have shown diuretics add an antihypertensive effect to every class of agent.
Black patients are good candidates to switch to diuretics because studies show their salt sensitivity makes them especially responsive to the drugs.
Here are some switching considerations for specific drugs:
ACE inhibitors. Dr. Moser said he probably would not switch patients from ACE inhibitors if the drugs are controlling blood pressure and the patient feels well. As a general rule of thumb, he would keep patients on their medications if their blood pressure is around 125-130 over 80-85. If he can't get the patient's blood pressure below 140/90, however, he would add a diuretic.
There is one group that researchers say you should definitely consider switching from ACE inhibitors to diuretics: black Americans. ALLHAT found diuretics lowered systolic blood pressure 4 mm Hg more than ACE inhibitors, probably because black Americans' salt sensitivity makes them especially responsive to diuretics.
Even more significantly, the study found that black Americans taking ACE inhibitors experienced a stroke 40% more often than their counterparts taking diuretics. (Black Americans typically require high levels of ACE inhibitors to control their blood pressure.)
Black Americans responded so well to diuretics in the ALLHAT study that some physicians questioned whether the high percentage of blacks in the study (35%) skewed the overall results against ACE inhibitors. An Australian study on hypertension published in the Feb. 13 New England Journal of Medicine seemed to lend some credence to that assertion.
The Australian study found that when compared with male patients on diuretics, male patients on ACE inhibitors had 17% fewer cardiovascular events, even though blood pressure was controlled equally well in both groups. (The study population was 95% white.) Based on this study, the ALLHAT numbers for events on ACE inhibitors may be a little high.
(Dr. Moser pointed out that in the Australian study, ACE inhibitors were more effective in only men. He characterized this finding as "difficult to explain.")
Calcium channel blockers. Dr. Moser said he would consider switching patients to diuretics from CCBs for two reasons: Diuretics cost less, and they have a lower incidence of heart failure. (He also noted that he would consider adding a diuretic if the CCB was not controlling the patient's blood pressure.)
Dr. Moser added that in many patients, the question of which drug is best is moot. He said that these individuals will need two or more medications to control their blood pressure, and one should be a diuretic.
Dr. Cushman said that even if CCBs are controlling your patients' blood pressure, you should consider switching them to a diuretic. He pointed out that ALLHAT patients taking CCBs who had excellent blood pressure control still experienced heart failure. Because you cannot tell which of your CCB patients will experience heart failure, Dr. Cushman said, you should consider switching them to diuretics.
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.
If clinical issues have you on the fence about switching patients from angiotensin-converting enzyme (ACE) inhibitors or calcium channel blockers to diuretics, the cost of the medications may help you decide the issue for some patients. At drugstore.com, diuretics cost $22 to $36 per year, ACE inhibitors range from $282 to $532, and calcium channel blockers cost between $584 and $679 per year.
"If a patient pays out of pocket for medications, a diuretic could be the difference between getting treatment and control vs. not getting control," said Paul K. Whelton, MD, professor of epidemiology and medicine at Tulane University in New Orleans.
Richard B. Whiting, FACP, chief of medicine and cardiology at St. Mary's Health Center in St. Louis and Governor for the College's Missouri Chapter, said that he would generally hesitate to switch controlled patients who have suffered no side effects. After the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial, however, he said that he might discuss diuretics with underinsured patients.
"I'd tell them I have confidence in the drug they are on," Dr. Whiting said, "but that excellent data show another will work very well and is a lot cheaper."
Because diuretics cost less and are much older than ACE inhibitors and calcium channel blockers, patients switched to diuretics from more high-profile drugs may think they are getting substandard care.
Marvin Moser, FACP, a clinical professor of medicine at Yale University, said it is vital to dispel the notion that diuretics represent substandard care.
"We aren't advocating good medicine for people who can afford it and bad medicine for people who can't," he said. "The data are clear: The less expensive medication is at least as good."
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