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Dr John La Puma

Blood-Pressure Study Finds

Blood-Pressure Study Finds
Cheap Diuretic May Be Best

Unusual Boost for Generics
Over Industry Blockbusters
By RON WINSLOW and SCOTT HENSLEY
Staff Reporters of THE WALL STREET JOURNAL

In a finding sure to shake up the $20 billion market for blood-pressure medicines, a 10-cents-a-pill diuretic proved superior to two of the pharmaceutical industry’s biggest-selling classes of drugs in a major U.S.-funded study.

The 33,000-patient study known as “Allhat” shows that diuretics — a 50-year-old product popularly known as “water pills” — are just as effective in preventing heart attacks as pills known as calcium channel blockers and ACE-inhibitors. These blockbuster drugs range in cost from 50 cents to nearly $2 a piece. Moreover, patients taking the diuretic were less likely than those on the other pills to suffer heart failure, strokes and other complications of hypertension.

The findings have important implications for the 50 million Americans and hundreds of millions of others around the world who suffer from high blood pressure, or hypertension — one of the main precursors of cardiovascular disease, the Western world’s leading killer. (See related article.) Most patients newly diagnosed with high blood pressure should be started on a diuretic, the study’s leaders say.

Billions for Branded Medicines

Perhaps equally important are the implications for pharmaceutical research. At a time when most research is done under the auspices of giant drug companies, which spend billions of dollars on the promotion of high-profit branded medicines, the Allhat study raises questions about whether the system overlooks cheaper generic alternatives. It has also kicked off a debate about the role government research should play in seeking answers to important medical and economic questions that industry-sponsored trials typically don’t address.

“We’re seeing these big areas where millions of people were being treated and we didn’t really know what approach was better,” says Robert Califf, head of the Duke University Clinical Research Institute. “You’d like your doctor to recommend what is best for you based on knowledge, not on what a drug company sales rep told him.”

The National Institutes of Health’s National Heart, Lung and Blood Institute spent $120 million to conduct the eight-year study at 623 clinics throughout North America, an ambitious project that no generic drug maker would ever be able to mount.

The results provide provocative answers to two questions that hundreds of drug industry-sponsored studies of blood-pressure pills have rarely ventured to ask: Which of the various types of medications on the market is best for patients, and do the newer, more expensive brand-name drugs offer advantages over the unheralded older remedies?

‘The Best Choice’

“Allhat shows that diuretics are the best choice to treat hypertension, both medically and economically,” Claude Lenfant, director of the National Heart, Lung and Blood Institute, told a press conference Tuesday in Washington, where the results were unveiled in advance of their publication Wednesday in the Journal of the American Medical Association.

Diuretics reduce levels of fluid and salt in the body, and help reduce blood pressure by causing constricted artery walls to relax. Though they have been around for 50 years, researchers remain at a loss to understand exactly how they do that.

The results pose a challenge to several drug makers, including Pfizer Inc., Merck & Co. and Novartis AG, whose sales of brand-name high-blood-pressure medicines could suffer if doctors embrace diuretics and other cheap generics as their principal therapies. All told, there are more than a half-dozen different classes of blood-pressure drugs on the market, and they have long been a major driver of pharmaceutical-industry sales and profits. Lisinopril, marketed by both Merck and AstraZeneca PLC, had peak annual sales of more than $1.5 billion before it went off patent earlier this year. Both drugs were used in the study.

For Pfizer, maker of Norvasc, a calcium channel blocker that was one treatment option in the Allhat study, the results were mixed. The data show the diuretic is the first choice for treatment but also confirm the safety of Norvasc, Pfizer’s second-biggest drug after the cholesterol fighter Lipitor, with $3.58 billion in sales last year. Previous research had suggested a higher risk of heart attacks for patients on Norvasc.

The Pharmaceutical Research and Manufacturers Association, the trade group for the brand-name drug industry, acknowledged that the study provides new information for physicians to consider when treating patients, but added, “not all patients with the same disease respond equally to the same medicines.” In a statement, the organization also said: “Our companies have spent billions of dollars on antihypertensive research over the last 25 years and have succeeded in giving the medical community a wide range of treatment choices for high blood pressure.”

‘Landmark’ Study

Study leaders and other clinicians hailed the results. “You could use the term ‘landmark,’ ” says Lawrence J. Appel, professor of medicine and a hypertension expert at Johns Hopkins Medical Institutions, Baltimore, who wrote an editorial accompanying the JAMA report. “There is no cost-quality trade-off on this. It’s quality and it’s cost. It’s hard to argue against that.”

The failure of ACE inhibitors to prevail is especially surprising to many doctors because those pills were developed to block the hormone angiotensin in the wake of new discoveries about how that powerful constrictor of blood vessels causes hypertension.

Researchers took care to explain that the findings aren’t an indictment of the other drugs. Both calcium channel blockers, which relax blood vessels by inhibiting the buildup of calcium in the artery walls, and ACE inhibitors have been shown in other studies to reduce major complications of high blood pressure. But in those trials the drugs were tested against a placebo or dummy pill, not against other agents.

Diuretics were once one of the drug industry’s main profit engines. But because their patents expired years ago, there hasn’t been any incentive for the pharmaceutical industry to mount new studies to evaluate diuretics’ benefits or glean a better understanding of how they work. They are considered preferred first-line therapy under current blood-pressure-treatment guidelines, but in practice they’ve been eclipsed by newer, and pricier, calcium channel blockers and especially ACE inhibitors.

The drug industry has a big arsenal of strategies to push its branded products. In addition to ads that target consumers and physicians, it hires as consultants leading doctors as “thought leaders” who talk up the pills or the science behind the pills at medical meetings. The big drug makers provide 60% of the financial support for continuing-medical-education classes, often using the sessions to promote medicines as doctors keep their credentials up to date. They provide funding for patient-advocacy groups that in turn help to promote newer, more-expensive medicines. And they use sophisticated marketing campaigns to persuade doctors and patients to switch to new, but similarly effective compounds when patents on big-selling drugs are about to expire.

Lacking a corporate advocate in such a marketplace, and with a medical culture that favors new, modern products, “the older drugs are going to get left behind whether they’re better or not,” says Dr. Califf.

It is hard not to see the industry’s marketing prowess at work: In 1982, according to a study cited by Allhat researchers, 56% of prescriptions for hypertension were written for diuretics. Both ACE inhibitors and calcium channel blockers made their entrance during the 1980s. By 1992, diuretics amounted to 27% of prescriptions.

All are “good products and provide physicians with a much better armamentarium with which to manage high blood pressure,” says Paul Whelton, senior vice president, health sciences at Tulane University in New Orleans and a coordinator of Allhat. “Yet there is always that nagging question: Does it really matter what agent we’re using first?”

The Allhat researchers say the answer is a resounding yes. Participants in the study — officially the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial — were age 55 or older with blood pressure above 140/90 and at least one other risk factor for cardiovascular disease, such as diabetes or smoking. Nearly half the patients were women, 32% were African-American and 16% were Hispanic, a diverse group of participants that indicates the results can be applied broadly across the population, researchers say.

Patients were selected randomly to start therapy on one of the three drugs and neither the patients nor their doctors knew which treatment they got. This so-called randomized double-blind design is considered the gold standard for clinical trials.

In the study’s principal finding, 11.5% of patients who received the diuretic chlorthalidone suffered either a fatal or nonfatal heart attack within six years, compared with 11.4% of those given lisinopril and 11.3% of those who were on amlodipine. That is as close to a tie as you can get in a clinical trial.

But in other indicators of effectiveness, the patients on either the calcium channel blocker or the ACE inhibitor were slightly less successful in lowering their blood pressures as those on the diuretic — a result that appeared to translate into higher complications from the condition. Patients on the calcium channel blocker had a 38% higher risk of heart failure, while those on lisinopril had higher rates of heart failure, stroke and a measure of combined cardiovascular complications.

Black patients, who are more likely to be salt-sensitive than whites, did especially well on diuretics, and those assigned to the ACE inhibitor group had a significantly higher rate of stroke.

Not for Everybody

Doctors caution that diuretics aren’t for everybody. The pills may cause dizziness, elevated blood sugar or decreased blood potassium, which can cause irregular heartbeats or muscle weakness. But study leaders said the drugs were at least as well tolerated as the comparison medicines.

Beyond the data, researchers say Allhat serves as a test case for how the government could run other studies seeking answers to important medical and economic questions that industry-sponsored trials typically don’t address. Most major studies are conducted with help of academic medical centers accustomed to enrolling patients and following treatment protocols. By contrast, most of the 623 sites participating in Allhat were primary-care clinics where doctors had limited if any experience in recruiting patients, and where the results more clearly reflect actual clinical practice.

HEALTH INDUSTRY EDITION

• Statin Study Yields Contrary Data

Read the full results of the Allhat report.

* * *

For more health coverage, visit the Online Journal’s new Health Industry Edition at wsj.com/Health, and receive daily Health e-mails.

“We got the answer to an important question and we documented that the model works,” says Dr. Whelton.

The question is, can or should the NIH make a habit of the studies? Dr. Lenfant, for one, believes the NIH should conduct Allhat-type drug studies only to solve major scientific questions with important public-health implications, but not ones that are principally economic.

Still, the NIH recently funded a study that debunked the widely held theory that hormone-replacement therapy protects women against heart disease. And another trial comparing the performance of various antipsychotic drugs for schizophrenia is under way.

Duke’s Dr. Califf says it isn’t reasonable to expect the pharmaceutical industry to conduct head-to-head studies needed to answer questions of both science and money. “It’s sort of an all-or-nothing game,” he says. There is a potential gain for the winner but a huge risk for a loser. Some results could essentially kill the market for a drug. “The industry can’t afford to take that kind of risk,” he says.

He believes the NIH or another public entity should set the agenda for the top public-health questions such studies could address and design the studies needed to get the answers. Drug companies should foot much of the bill, he says.

Even if the NIH shouldered more responsibility for such studies, there is the problem of disseminating the results and persuading doctors to change practice. Allhat lacks the advantage of a big brand-name drug to build momentum to change practice. “The winner here is a low-cost generic for which there is no sales force,” says Johns Hopkins’ Dr. Appel.

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Dr John La Puma

Does Vitamin C Lower Blood Pressure

Fruits, veggies help lower blood pressure
By SALLY SQUIRES
Washington Post
If you’re looking for more motivation to eat those five servings a day of fruit and vegetables, here’s something that may help: A growing body of evidence suggests that people who eat enough fruits and vegetables to meet the daily requirements for vitamin C have healthier blood-pressure levels than those who skimp on these important foods.

In a study published earlier this year, Gladys Block, professor of public health nutrition at the University of California, Berkeley, took a group of healthy men with normal blood pressure and fed them a diet low in vitamin C for 30 days. For the next 30 days, the men ate food high enough in vitamin C to provide 117 milligrams a day. That slightly exceeds the recommended intake set by the National Academy of Sciences, which is 90 milligrams for men (or roughly that found in 6 ounces of orange juice) and 75 milligrams per day for women ages 19 and older.

Blood pressure was checked throughout the study. Block found that diastolic blood pressure — that’s the pressure exerted on blood vessel walls when the heart rests between beats, and it’s the lower number in a blood pressure reading — rose and fell significantly along with the intake of foods rich in vitamin C.

As she reported in the Annals of the New York Academy of Sciences, people with the lowest vitamin C blood levels “had the highest blood pressure one month later.” In fact, those with the very lowest blood levels of vitamin C had diastolic blood pressure that was 7 milligrams higher than participants in the study who had the greatest intake of vitamin C.

The study also looked at age, body mass index and intake of additional key nutrients, including calcium, fiber, sodium and potassium and found that all were less powerful in affecting blood pressure than foods containing vitamin C. (And Block says she has recently completed a study of women that found similar effects.)

Estimates are that the average intake for Americans is about 100 milligrams of vitamin C per day — enough to meet the recommended daily intake.

But Block notes that this average “obscures the fact that substantial numbers of people actually have habitually low-intake levels” of vitamin C. Among the groups that often fall short are African-Americans, who also have a high incidence of high blood pressure. Block’s theory? “Low intake of antioxidant-rich fruit and vegetables may be one of the causes of hypertension,” she suggests.

There’s plenty of reason to pay attention to that finding even if you’re not yet one of the estimated 50 million Americans with hypertension.

Being overweight or obese increases the risk of high blood pressure. Blood-pressure levels also rise with age, and an estimated 23 million Americans already have high-normal blood pressure (that means a systolic pressure of 130 to 139 milligrams and/or diastolic of 85 to 89 milligrams).

People with high-normal blood pressure are up to 2.5 times more likely to suffer a heart attack, stroke or other cardiovascular problem within the next 10 years than those with normal blood pressure, according to the National Heart, Lung and Blood Institute.

The good news: Eating five servings of varied fruits and vegetables a day provides about 200 milligrams of vitamin C, according to Mark Levine, chief of molecular and clinical nutrition at the National Institute of Diabetes, Digestive and Kidney Diseases. (A serving is equal to one medium piece of fruit, a quarter-cup of dried fruit, a half-cup of fresh, frozen or canned fruit, or 6 ounces of vegetable or fruit juice.)

And if you’re looking for more ways to stay healthy by eating a well-balanced diet, take a look at the Dietary Approaches to Stop Hypertension (DASH) — a reduced-fat program developed by the NHLBI. For details, see www.nhlbi.nih.gov/health/public/heart/hbp/dash.

In DASH, the goal is to eat low-calorie, filling foods in place of high-calorie fare. DASH includes nine to 10 servings a day of fruits and vegetables as well as whole grains, low-fat or nonfat dairy products, fish, poultry and lean meat, plus about a serving a day of nuts or beans. Fat is limited to about 27 percent of daily calories, with no more than 7 percent of calories from saturated fat.

Studies show that DASH not only substantially lowers blood pressure but also reduces blood cholesterol levels and cuts homocysteine — another risk factor for heart disease.

“The nice thing about DASH is that you get a lot of food,” says Edward Roccella, coordinator of the NHLBI’s National High Blood Pressure Education Program. That’s because many of the foods included in the DASH program — especially fruits and vegetables and whole grains — are lower in calories than high-fat foods, so it’s possible to eat more of them. And since they are high in volume and fiber, they also may make you feel fuller.

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Dr John La Puma

Nutrients Are Key to Preventing Cancer

Nutrients Are Key to Preventing Cancer
Associated Press

By LAURAN NEERGAARD AP Medical Writer

Tuesday, December 3, 2002

WASHINGTON (AP) – Can a diet rich in a particular nutrient really prevent cancer? The government is recruiting 32,000 middle-aged men to see if selenium or vitamin E can prevent prostate cancer, the biggest clinical trial yet to address such dietary questions.

It’s just a first step toward what could become a major change in nutrition: Preliminary but intriguing genetic research suggests certain nutrients may prove more cancer-protective for one person than the next – suggesting that one day doctors might write prescriptions for diets to prevent tumors in certain people.

“The future is tailored recommendations,” John Milner of the National Cancer Institute says about this fledgling new science, “nutrigenomics.” “That’s the excitement.”

Cancer doesn’t just arise overnight. A few tiny cells gone wrong slowly grow over decades. Whether the result is a life-threatening tumor depends on genes and environment – including food.

Up to 35 percent of cancers are related to dietary habits, says Milner, chief of NCI’s research into nutrition and cancer prevention.

That doesn’t mean an occasional cheeseburger or doughnut is dooming. But study after study links lifelong diets high in plant foods to lower cancer rates.

Also, people who eat lots of fruits and vegetables generally are skinnier. Obesity increases risks of cancers of the uterus, gallbladder and possibly colon and prostate, while a large weight gain after reaching adulthood is linked to breast cancer.

Armed with such provocative evidence, scientists now are trying to tease out which of the myriad nutrients and chemicals in different foods are most protective – and why, at a genetic level, they do the job.

It’s exceedingly complex research. Not everybody gets equal benefit from nutrient-rich diets, a discrepancy that probably points to genetic variability. For example, scientists studying lung cancer rates in part of China found people with the lowest cancer risks also were genetically deficient in an enzyme that metabolizes certain nutrients in cruciferous vegetables.

In other words, those lucky people’s genes seemed to make broccoli better for them.

Similar links to cancer are being explored with genes that metabolize alcohol, folate from grains and other food chemicals.

“In five years, we’ll have a lot of information on how your gene profiles influence your response” to different foods, Milner predicts.

But first, scientists need hard proof of which of the many nutrients commonly considered protective truly are, and at what levels. Small studies promoting 12 cups a day of tea or three whole garlic cloves daily aren’t too practical for many people.

Until now, most food and cancer research has focused on animals or merely monitoring people’s diets and their later health, which gives only clues, not proof. Plus, too much of some nutrients can be dangerous.

Top of the federal research list: selenium, a trace element found in grains and meat. Previous studies suggest that eating 200 micrograms of selenium a day, about twice the national average, might lower the risk of prostate, lung and colorectal cancer, perhaps by slowing abnormal cell growth or activating tumor suppressor genes.

To prove the prostate benefit, NCI is recruiting 32,400 healthy men in their 50s to take for the next seven years either selenium; 400 milligrams of vitamin E, another nutrient linked to lower prostate risk; both; or a dummy pill.

Too much is toxic, so don’t pop lots of selenium supplements, cautions NCI researcher Cindy Davis.

Lycopene, the chemical that makes tomatoes and watermelon red, is another top prospect. Cooking tomatoes with a little oil – think spaghetti sauce – significantly increases lycopene absorption. In one study, it decreased prostate cancer by 35 percent. The NCI has begun small clinical trials to find lycopene’s maximum safe dose and see if giving it to prostate cancer patients before surgery helps stem their disease.

Despite lots of hype, research is much more mixed on other foods. Soy, for instance, is widely touted as protective against breast cancer, but women seem to get the benefit only if they eat soy before puberty, says NCI researcher Harold Seifried.

It will take years to sort out what are truly anticancer diets. For now, the American Cancer Society’s best advice: Eat a wide variety of foods, including at least five servings of fruits and vegetables a day, and slim down.

EDITOR’S NOTE – Lauran Neergaard covers health and medical issues for The Associated Press in Washington.

On the Net: www.clinicaltrials.gov

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