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Common heart failure drugs can be safely used at higher, more effective doses, study says

University of California - San Francisco

Commonly prescribed heart failure drugs known as ACE inhibitors are often given at lower doses than recommended by leading cardiology associations. A new study of the ACE inhibitor lisinopril written by a researcher at San Francisco VA Medical Center and University of California, San Francisco shows that the vast majority of heart failure patients can safely tolerate higher doses, which have been proven to reduce death and hospitalizations significantly.

The research is published in the latest issue of the Archives of Internal Medicine, written by Barry Massie, MD, SFVAMC chief of cardiology and UCSF professor of medicine, on behalf of the group of researchers who conducted the Assessment of Treatment with Lisinopril and Survival (ATLAS) trial.

Although a number of different ACE inhibitors have been proven in clinical trials to reduce mortality in heart failure patients, a majority of physicians who prescribe these drugs use lower doses than were shown to be effective in clinical trials, Massie said. These doctors have been concerned that the drugs might dangerously lower patients' blood pressure, impair kidney function, or greatly elevate potassium levels, he said.

The new study showed that for a great majority of patients, going from a low dose to a high dose did not cause these severe side effects. "As a rule, giving patients the full recommended dose of ACE inhibitors should cause relatively few problems, if given properly and according to previous studies will reduce deaths and hospitalizations," Massie said.

Nearly five million Americans currently have congestive heart failure, and nearly 50,000 die of the disease each year, according to the American Heart Association. Roughly 70 percent of heart failure patients are prescribed an ACE inhibitor, said Massie.

In this study, Massie and his colleagues performed a secondary analysis of data from the ATLAS trial, a randomized clinical trial of lisinopril, one of the most popular ACE inhibitors. The trial compared relatively high doses (35 milligrams) to lower doses (5 milligrams).

The primary results of the study, published in December 1999, had shown that the higher dose gave greater benefits to heart failure patients than the lower dose. Patients taking higher doses had a slightly lower death rate, Massie noted. And although this decrease was not statistically significant, the higher dose reduced the rate of hospitalization for heart failure by 24 percent, suggesting that lower doses did not give patients the drug's full benefits.

The new study by Massie and his colleagues looked at side effects of the drug, such as sharp decreases in blood pressure and increased levels of creatinine, a marker of kidney dysfunction. ACE inhibitors are known to decrease blood pressure by shutting off an enzyme system that leads to blood vessel constriction.

They found that patients who received the higher doses had, on average, only slightly lower blood pressure and only slightly higher creatinine levels, which could nearly always be managed by reducing the dose instead of halting ACE inhibitor treatment.

If the drugs had increased negative side effects one might expect that higher doses would have caused more patients to withdraw from the trial. Instead, a higher percentage of low dose patients (31 percent) withdrew compared with 27 percent in the high dose group, the researchers found.

Furthermore, an analysis of patients who might be considered to have a higher risk of side effects, such as older patients, those with lower blood pressure, diabetics, and those with preexisting kidney dysfunction, did not have a substantially higher risk. "Even in these high risk categories, more than 95 percent of patients can continue to tolerate their assigned dose of the drug," Massie said.

The "high" dose of 35 mg used in this study is higher than the 20 mg dose usually recommended in guidelines, Massie noted. However, the average dose prescribed by physicians is even lower, between 5 and 10 milligrams, he said.

"The recommendations say doctors should work their patients up to 20 milligrams of lisinopril to get the full benefits of the drug. This study shows that a vast majority of patients can be safely titrated to these doses," Massie said.

However, the higher doses of ACE inhibitors aren't right for all heart failure patients, Massie said. "A few people do have problems, such as blood pressure going too low. And in those cases you can simply decrease the dose to avoid trouble," he said.

The important lesson here, he said, is that the fears that many doctors have about prescribing the full recommended dose of ACE inhibitors are not justified for most patients. With respect to kidney failure, ACE inhibitors may actually help rather than hurt. "It's paradoxical that doctors were afraid these drugs would cause kidney failure because in diabetics and people with kidney disease the drugs have actually been shown to delay the progression of kidney dysfunction," he said.

Co-authors on the study include Milton Packer, MD, professor of medicine and chief of the division of cardiovascular physiology at Columbia University College of Physicians and Surgeons; Paul Armstrong, MD, chairman of the department of medicine at University of Alberta; John Cleland, MD, professor of medicine at University of Hull in the United Kingdom; John Horowitz, MD, professor of cardiology at University of Adelaide in Australia; Philip Poole-Wilson, MD, professor of cardiac medicine at Imperial College School of Medicine at University of London; and Lars Ryden, MD, professor of medicine at the Karolinska Institute in Stockholm, Sweden.


This study and the ATLAS trial were funded by Astra-Zeneca, a pharmaceutical company that makes and sells lisinopril.

Barry Massie was a member of the steering committee of the ATLAS trial and served as a consultant to Astra-Zeneca during the study.

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