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ATLAS study ends with FDA application
Those higher dosages of lisinopril that you’ve been seeing may soon gain official approval by the Food and Drug Administration (FDA). AstraZeneca Pharmaceuticals in Wilmington, DE, filed a supplemental new drug application with the agency a few months ago to request approval for the use of its long-acting ACE inhibitor Zestril (lisinopril) at doses of up to 35 mg once daily in the management of heart failure.
Lisinopril already is indicated as adjunctive therapy in the management of heart failure for patients not responding adequately to diuretics and digitalis. The drug also is indicated for treating hypertension and improving survival of hemodynamically stable patients within 24 hours of heart attack. Its usual effective dosage range CHF patients is 5 mg to 20 mg, once daily. But cardiologists have been prescribing larger doses all along, says David S. Roffman, PharmD, BCPS, associate professor of pharmacy practice and science at the University of Maryland’s School of Pharmacy in Baltimore and therapeutic consultant for the medical system’s cardiac care unit.
"Cardiologists typically give high doses of ACE inhibitors anyway," he says, "based on the premise that higher doses — if they are tolerated, and they usually are — do more for symptomatic improvement than lower doses." He says physicians have the prerogative to use meds in a way they think is appropriate for patients, irrespective of FDA-approved labeling.
"The majority of physicians will, on occasion, use a drug for a non-FDA-approved indication in a dose that is not necessarily FDA-approved because they see evidence for its benefit in the literature," says Roffman. Off-label use of drugs is not an uncommon phenomenon. The most recognized example is the use of nitrates for heart failure; they are not labeled for the condition, yet prescribed frequently. There is literature justification for their use, so physicians don’t have medical malpractice concerns.
The FDA does not require that a manufacturer change its dosage every time the literature shows an indication that’s not on the label. And conversely, a manufacturer doesn’t want to change its label each time, either, because of the expense involved. "Cardiologists who are aware of the burgeoning literature on improved symptoms with higher doses will, with justification, use higher doses," says Roffman.
Then why is the company going to the trouble of submitting the supplemental new drug application? "It’s a good thing to educate physicians that higher doses, when tolerated, are good for patients’ symptoms and even for survival," he says. And, of course, it’s good for marketing.
The ATLAS trial
AstraZeneca’s rationale for the label change is based on the results of a five-year clinical trial, ATLAS (Assessment of Treatment with Lisinopril and Survival) which evaluated the effect of low (2.5 mg to 5 mg) vs. high (32.5 mg to 35 mg) doses of lisinopril on mortality and morbidity in more than 3,000 patients with CHF. ATLAS study results were first presented last year at the 47th annual American College of Cardiology scientific session in Atlanta, and they indicated a 12% risk reduction in all-cause mortality and all-cause hospitalizations when patients were treated with higher doses.
Raymond Urbanski, MD, associate medical director at AstraZeneca, explained the complexity of determining ideal dosages for CHF: "For a condition like hypertension, you can monitor a patient’s blood pressure and adjust the dose that way. But in patients with heart failure, you’re not sure what dosages are more or less effective because you don’t have such a simple marker as you do with hypertension. Instead, you have to look at different specific dosage levels and then look at outcomes data — morbidity and mortality statistics — to ascertain what doses are more efficacious."
That was the rationale for the ATLAS study. "Based on that data," he says, "it appears that higher doses [of lisinopril] produce a better outcome with regard to morbidity and mortality than lower doses." The dose-response relationship between lisinopril and its mechanism of action in CHF — its effect on the left ventricular remodeling process — is not known. It appears that lisinopril acts at the cardiac level by altering some of the neurohumeral factors that are involved in worsening heart failure. "We don’t know the dose-response relationship to that," he says, "but based on the ATLAS data, it appears that higher doses are efficacious in counteracting that pathologic process, and that low doses, while effective, are not as effective as the higher doses."
Urbanski says that side effect profiles of the high and low doses are essentially the same. "There was slightly more hypotension in the higher doses in the ATLAS trial, but that’s to be expected. Most ACE inhibitor side effects tend to occur early in therapy with the initial doses."
"There is symptomatic improvement when lisinopril dosage is increased to the 40 mg level," Roffman explains. "Whether that improvement could be translated to mortality in a larger study is unknown at this point, but early indications from ATLAS imply that patients who don’t get systematic improvement on 20 mg of lisinopril, for example, may experience improved symptoms when the dosage is increased to 40. That is the impetus for AstraZeneca’s application to the FDA for increasing the dose."
He says that while many CHF cardiologists have been prescribing 40 mg doses of Prinivil or Zestril for a long time despite FDA approvals, "unfortunately, in the community population, people are put on small doses of ACE inhibitors and left on them."
Why? In a 1996 editorial review of the then-ongoing ATLAS trial, Milton Packer, MD, lead investigator, said that the preference for low doses is based on the belief that low and high doses exert similar benefits, but that high doses produce more side effects.1
"Yet most studies indicate that large doses of ACE inhibitors produce greater hemodynamic and clinical effects than small doses with no additional toxicity," he wrote.
It was uncertain whether survival effects of the drugs are also related to dose, and it was that question that launched the ATLAS trial — it compared the effects of low and high doses of lisinopril on the survival of patients with heart failure. "If the study demonstrates that large doses are needed to produce optimal effects on mortality," wrote Packer, "then the low dose strategies now widely used in clinical practice may be inadvertently nullifying the enormous potential benefits that ACE inhibitors might otherwise have."
Roffman concurs that a major concern in prescribing higher doses is that they may increase the risk of side effects. "A significant number of patients in heart failure Class III or IV have relatively low blood pressure due to poor pump function. There’s a hesitancy on the part of physicians — mostly internists or family doctors — to push the drug in someone who’s blood pressure is 90/60 even though the data say that most such patients tolerate higher doses without symptomatic hypotension."
Administration of lisinopril to patients with hypertension results in a reduction in blood pressure to about the same extent in both reclining and standing positions with no compensatory rapid heart beat. In patients receiving digitalis and diuretics, single doses of lisinopril result in decreases in blood pressure and systemic vascular resistance, accompanied by an increase in cardiac output but no change in heart rate.
Adverse reactions are usually mild
Roffman says another concern is that higher doses will decrease renal function in CHF patients who have some renal insufficiency to begin with. But aside from the renal concerns, he says, there is a greater overriding problem in this type of drug therapy — its underuse.
"The bigger issue is that only 30% to 50% of CHF patients are on ACE inhibitors at all" says Roffman. "Half the people who ought to be on the drugs aren’t."
Originally approved by the FDA in 1987, Zestril is now the most prescribed ACE inhibitor on the American market and is available by prescription in packages of 100 tablets in strengths of 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, and 40 mg. In patients with heart failure and renal impairment of hyponatremia, the drug should be initiated at 2.5 mg to 5 mg once daily under close supervision, then titrated upward until blood pressure is controlled. According to AstraZeneca, Lisinopril has been well-tolerated in controlled clinical trials of patients with hypertension or CHF. The drug suppresses the renin-angiotensin-aldosterone system to reduce blood pressure, with an onset of action with one hour.
ACE inhibition limits the conversion of angio-tensin I to angiotensin II, resulting in decreased plasma angiotensin II, reduced vasopressor activity, and lower aldosterone levels, according to literature distributed by AstraZeneca. Angiotensin II is a potent vasoconstrictor that increases blood pressure and fluid retention that may play a role in CHF. Adverse experiences are generally mild and transient, the most frequent being dizziness, headache, fatigue, diarrhea, upper respiratory symptoms, and cough. Lisinopril is also marketed by West Point, PA-based Merck as Prinivil.
[For information on Zestril, call (800) 456-3669, ext. 2231; www.usa.zeneca.com/pharm/pibs/pib_ zestril.htm. For information on Prinivil, call (215) 652-5000; www.merck.com.]
1. Packer M. Do angiotensin-converting enzyme inhibitors prolong life in patients with heart failure treated in clinical practice? J AM Coll Cardiol 1996; 28:1,323-1,327.
• VanVeldhuisen D, Genth-Zotz G, Brouwer J, et al. High- versus low-dose ACE inhibition in chronic heart failure. J Am Coll Cardiol 1998; 32:1,811-1,818.