ACE Inhibitors should have been Banned for Pregnant Women

In a group of 209 babies born to women taking ACE inhibitors in the early stages of pregnancy, a recent study published in the June 8, 2006 New England Journal of Medicine, reported that 18 or 7.1% of the infants, were born with serious birth defects.

Data for the study were obtained from the Tennessee Medicaid database for the years between 1985 and 2000, which allowed for the examination of the prenatal record as well as infant outcomes.

Pharmacy records were also reviewed and the fetus was considered to have an exposure to an ACE inhibitor if the mother filled a prescription for the drug during the first trimester of pregnancy. Mothers with evidence of diabetes were excluded from the study, and infants exposed to antihypertensive medications after the first trimester or to other teratogenic agents during gestation were also excluded.

To reach the outcome, the study's authors compared infants exposed to ACE inhibitors with a cohort of children whose mothers received other antihypertensive drugs and a group of infants not exposed to any antihypertensive drugs. Most of the infants in the ACE group had been exposed to at least 2 months of the drug.

The study determined that infants exposed to ACE inhibitors were almost 4 times more likely to suffer cardiovascular problems and nearly 5 times more likely to have central nervous system malformations when compared to infants exposed to other medications or no antihypertensives drugs at all.

The study employed the definitions of the Centers for Disease Control and Prevention for major malformations. The cardiovascular malformations observed were mainly atrial and ventricular septal defects and patent ductus arteriosus. The CNS malformations included spina bifida and significant eye defects. Two cases of renal dysplasia and some intestinal malformations were also present.

One-third of the birth defects involved the heart, one-quarter the limbs or the face, and one-tenth involved the brain or spinal cord. Some defects, such as the heart problems, might be curable with surgery or other treatment, but others resulted in retardation or permanent disability.

The study's findings were corroborated by blinded investigators reviewing the medical records, and the comparison of the 3 groups was adjusted for other risk factors for malformation.

Based on these findings, taking ACE inhibitors during early pregnancy "cannot be considered safe and should be avoided," according to Dr William Cooper, a pediatrician at Vanderbilt Children's Hospital in Nashville, and leader of the study.

Critics say the fact that such serious findings are only first recorded 25 years after the ACE inhibitors came on the market demonstrates the inability to collect safety data on the ill-effects of drugs used during pregnancy.

Prior to FDA approval, new drugs are tested on pregnant animals to see whether they cause birth defects because it is considered unethical to include pregnant women in clinical trials unless the drug is intended to treat a pregnancy-related condition.

Studies of large databases such as Medicaid records that show pregnant women already taking a medication are about the only means available to measure risks to the fetus from a particular drug.

In an editorial accompanying the study in the NEJM, Dr J M Friedman, MD, PhD, a medical geneticist at the University of British Columbia, said the ACE study highlights the larger problem about the lack of safety data. "Birth defects caused by teratogenic treatments are preventable," he wrote, "and babies and their mothers are being harmed unnecessarily because we do not know enough about which treatments to use and which to avoid."

"Further study is needed," he said, "to determine the precise risk and its relationship to individual drugs but the increase appears to be great enough to require discussion with all women of reproductive age who are prescribed ACE inhibitors."

"A woman who learns she is pregnant while taking an ACE inhibitor," Dr Friedman warns, "should immediately be switched to another antihypertensive agent to minimize the risk of fetopathy."

"Detailed fetal ultrasonography and echocardiography at about 18 weeks of gestation," he said in the NEJM, "should be offered to women who have taken such drugs in the first trimester of pregnancy." ACE inhibitors include:

• Capoten (captopril)
• Vasotec (enalapril)
• Prinivil, Zestril (lisinopril)
• Lotensin (benazepril)
• Monopril (fosinopril)
• Altace (ramipril)
• Accupril (quinapril)
• Aceon (perindopril)
• Mavik (trandolapril)
• Univasc (moexipril)

The alternatives drugs that doctors should prescribe for pregnant women with high blood pressure are diuretics, alpha-methyldopa, some beta-blockers, and the calcium-channel blocker nifedipine, according to FDA officials and Dr Friedman in his editorial.

But the fact remains that drug companies have known that these drugs posed a danger to the fetus and they should have been banned from use by all pregnant women 15 years ago. Claiming the drugs were not dangerous in the first trimester of pregnancy even though they were known to be lethal in the second and third trimesters, was just plain silly.

This is just another blatant example of drug companies putting profits over the lives of patients.

Besides there have been previous studied that have shown ACE inhibitors to cause birth defects in the first trimester of pregnancy. For instance, in the results of a surveillance study reported in 2002, on Michigan Medicaid patients, involving 86 newborns who were exposed to captopril during the first trimester of pregnancy, four or 4.7% of the infants, were found to have major birth defects, including one cardiovascular anomaly, one polydactyly, one limb reduction defect, and one hypospadias, as reported on the Canadian Family Physician web site.

In a review published by Briggs et al in 1998, of 40 newborns exposed to enalapril during the first trimester, four or 10% of the babies, had major birth defects, including two cardiovascular anomalies and one polydactyly.

The results of a study reported in 1998, on 15 newborns exposed to lisinopril during the first trimester, showed two, or 13.3% the infants, to have major birth defects, including one polydactyly, according to Briggs GG, Freeman RK, Yaffe SJ, Drugs in pregnancy and lactation, Baltimore, Md: Williams & Wilkins; 1998.

Intrauterine growth restriction, prematurity, persistence of patent ductus arteriosus, severe neonatal hypotension, neonatal anuria, and neonatal or fetal death have all been observed with the use of ACE inhibitors, reported by Barr M Jr, Teratogen update: angiotensin-converting enzyme inhibitors, Teratology 1994;50:399-409.

In 1997, animal data revealed increased morbidity and mortality in fetuses exposed to ACE inhibitors in utero. Decreased uteroplacental blood flow, low birth weight, hypotension, preterm delivery, and fetal death were noted by Mastrobattista JM. Angiotensin-converting enzyme inhibitors in pregnancy, Semin Perinatol 1997;21:124-34.

In 1994, a prospective placebo-controlled study of baboons was reported that showed a significant increase in fetal death or fetal growth restriction in 4 out of 13 baboons in the group treated with enalapril compared with no events among the controls, according to Harewood WJ, Phippard AF, Duggin GG, Horvath JS, Tiller DJ. Fetotoxicity of angiotensin-converting enzyme inhibition in primate pregnancy: a prospective, placebo-controlled study in baboons (Papio hamadryas), Am J Obstet Gynecol 1994;171:633-42.

The FDA reported known risks back in a 1991 summary of 85 pregnancies during which women were exposed to ACE inhibitors, where 11 deaths occurred, including 6 stillbirths and five neonatal deaths, reported in the Journal Obstet Gynecol 1991;78:128-35.

Twenty-nine cases of perinatal renal failure in association with maternal use of ACE inhibitors were listed by the FDA in 1991. On March 13, 1992, the FDA announced that all ACE inhibitors, "will be required to carry a "boxed warning" on the label for women in the advanced stages of pregnancy."

"At the agency's request," the FDA said, "six pharmaceutical companies are simultaneously sending out a "Dear Doctor" letter emphasizing that women who take the drug in the second and third trimesters of pregnancy are running the risk of causing significant harm to fetuses, including kidney failure and face or skull deformities."

For several years, labeling for ACE inhibitors had warned of the risks, but the FDA noted that additional cases continued to be reported.

"More than 50 cases of fetal harm have been reported over the past several years," it noted. "The warnings in the labeling are therefore being strengthened by including a boxed warning and other changes."

Pharmacists were also alerted to the labeling change and were asked to counsel women of child bearing age who were taking ACE inhibitors. They were also provided stickers that read, "If you become pregnant consult your doctor promptly about switching to a different drug," to place directly on prescription bottles.

Companies required to send "Dear Doctor" letters were Bristol-Myers Squibb (Capoten, Capozide, Monopril), Ciba-Geigy (Lotensin), Hoechst-Roussel Pharmaceuticals (Altace), ICI Pharmaceuticals Group (Zestril, Zestoretic), Merck Sharp and Dohme (Vasotec, Vasotec I.V., Vaseretic, Prinivil, Prinzide), and Parke-Davis (Accupril).

There is absolutely no reason whatsoever that would justify prescribing ACE inhibitors to pregnant women other than to make more money because other drugs were found to be superior in treating hypertension four years ago.

In 2002, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, or ALLHAT, compared the three major classes of drugs used to treat high blood pressure, and reported that diuretics were the most beneficial as the initial treatment.

In addition, the results of the new analysis of ALLHAT, were published in the April 25, 2005 Archives of Internal Medicine, by lead author Jeffrey Cutler, a senior adviser at the National Hear, Lung and Blood Institute a unit of the National Institute of Health which determined that patients on diuretics had better blood pressure control, fewer strokes and less congestive heart failure than patients who were not on diuretics.

ALLHAT was a randomized, double-blind trial involving 42,418 patients, ages 55 and older. Of those, 31,512 subjects were assigned to a diuretic (chlorthalidone); a calcium channel blocker (amlodipine); an angiotensin converting enzyme (ACE) inhibitor (lisinopril). 13,101 had diabetes, 1,399 had elevated fasting glucose and 17,012 had normal glucose levels. Compared with the ACE inhibitor and the calcium channel blocker, the diuretic was:

• More protective against congestive heart failure in patients both with and without diabetes (by about 1/6 compared with the ACE-inhibitor, and by about 1/3 compared with the calcium channel blocker).

• More effective in lowering systolic blood pressure — the measure of blood pressure when the heart beats — among those with and without diabetes.

• At least equally protective against fatal coronary heart disease or non-fatal heart attacks in people with diabetes, those with elevated fasting glucose, and non-diabetics.

• Equally protective against death from all causes, end-stage kidney disease, or cancer in people with diabetes, those with elevated fasting glucose, and non-diabetics.

In the price comparison, a diuretic was found to cost as little as $36-$96 annually, while a calcium channel blocker such as Novarsc costs about $724 a year, and Accupril, an ACE inhibitor costs about $470 a year. Beta-blockers, which are earlier medications than the ACE inhibitors cost between $240-$667 per year.

In response to the new analysis of ALLHAT, the National Institute of Health announced that it would use about 600 medical professionals to spread the word to doctors that diuretics should be the first line of treatment used in the battle against hypertension.

Some states adopted the plan to fight the cost to Medicaid programs of expensive drugs being prescribed by doctors when other cheaper drugs can accomplish the same results.

The pharmaceutical industry has been very successful in convincing doctors to prescribe ACE inhibitors instead of less expensive drugs. In a survey conducted on 1,700 primary care doctors in 2003, diuretics were rated less effective at lowering blood pressure and beta-blockers were thought to have more side effects than calcium channel blockers and ACE inhibitors.

"These new, more expensive medications are being more heavily promoted by the drug companies, and one way or another that information influences how people perceive the drug's effectiveness," according to lead author Peter Ubel, MD, associate professor of internal medicine at University of Michigan Medical School.

The study, published in the December 2003 Journal of General Internal Medicine, presented doctors with a hypothetical patient whose blood pressure was 170/105, who had unsuccessfully tried to control his blood pressure for a year using diet and exercise and had no other medical problems.

Doctors were asked to estimate the effectiveness of diuretics, ACE inhibitors, beta-blockers, and calcium channel blockers and to say what drug they would prescribe to the patient.

Despite numerous studies to the contrary, the majority of doctors rated diuretics significantly less effective than the other 3 drugs, and said beta-blockers were more likely to cause side effects, and would prescribe ACE inhibitors as the first choice for treatment.

Even though, according to Dr Ubel, with the hypothetical patient, there would be no advantage in taking ACE inhibitors over diuretics or beta-blockers, and ACE inhibitors tend to have more side effects than diuretics or beta-blockers.

"They're also more expensive," Dr Ubel noted, "which could drive up the patient's bill at the drug store - or ultimately drive up insurance costs."

The survey found that physicians who favored prescribing the more expensive drugs were more likely to pass out free drug samples provided by drug company sales representatives.

"It may seem like the doctor's helping patients get more affordable medicine," Dr Ubel says, "but it's not a lifetime supply."

After the free samples run out, he notes, the patient is left to pay for a more expensive drug.

"The industry influence is pervasive," says Dr Ubel, who is also a research investigator at the Ann Arbor Veterans Administration Health Center. The University of Michigan Hospitals and Health Centers prohibits distributing drug samples to patients.

Another study presented at the March 4, 2004 American Heart Association's 44th Annual Conference on Cardiovascular Disease, Epidemiology and Prevention, determined that a third of the increase in the cost of treating high blood pressure between 1990 and 2002, was related to physician prescribing habits.

To reach this outcome, Randall Scott Stafford, MD, PhD, an assistant professor of medicine at the Stanford University Prevention Research Center, conducted an analysis of data from IMS Health's National Disease and Therapeutic Index, which included information on physician office visits, and the National Prescription Audit Plus, a survey of pharmacies.

The physician data included information on 17,318 office visits for the treatment of hypertension in 1990, and 21,885 patient visits in 2002. The pharmacy survey included information provided by 20,000 retail pharmacies.

The study looked at the total cost of drugs used in the treatment of hypertension and fond that in 2002, Americans spent $12 billion on drugs for high blood pressure, slightly more than double what was spent in 1990.

The two types of expensive drugs that contributed most to the cost increase were ACE-inhibitors and angiotensin receptor blockers (ARBs).

In 2002, a month's supply of ACE inhibitors was about $44, and a month of ARBs was about $56, compared to $9 for a diuretic. While ACE inhibitor and ARB use increased from 1990 to 2002, "the prescription of diuretics declined by about 50 percent during the same period," Dr Stafford determined.