Ketamine may be promising treatment for depression among patients with bipolar disorde

Moral of the story:  While it may sound scary, Ketamine has been used for a variety of purposes and may hold promise in an area still looking for a good drug.

Source: AMA Morning Rounds 8/3/2010

Ketamine may be promising treatment for depression among patients with bipolar disorder.

The Los Angeles Times (8/2, Roan) "Booster Shots" blog reported that the prescription medication ketamine [ketamine hydrochloride], which is "used as an anesthetic -- and used illegally as a party drug at raves -- may have a role in treating people with bipolar depression, according to astudy " published August 2 in the Archives of General Psychiatry. In a study of 18 patients, "researchers at the National Institute of Mental Health found that 71% of the bipolar patients who had not responded to other treatments, experienced significant improvement in depression symptoms after a single intravenous infusion of ketamine. Most of these patients responded within 40 minutes of receiving the drug," and the effects lasted for approximately three days.

        Time (8/3, Cloud) reports, "All patients were randomly and blindly given one 0.5 mg/kg dose of ketamine and one equal dose of placebo saline through an IV drip two weeks apart. Patients taking ketamine were significantly more likely than those on the placebo to show short-term improvement in their depression symptoms. This is crucial for bipolar patients who are in depressive crisis and at high risk of suicide: if you can give them something to block short-term suicidal impulses, you may be able to settle them -- and then treat them for long-term problems."

        "Ketamine acts on the brain's glutamatergic system, which plays a role in information processing and memory formation,"HealthDay (8/2, Preidt) reported. "Recent research suggests that dysfunction in this brain system may contribute to bipolar disorder, noted Dr. Nancy Diazgranados and colleagues at the US National Institute of Health." But, even though "ketamine has been used off-label as an experimental treatment for depression, it has not been approved by the US Food and Drug Administration for that use, according to the US National Institutes of Health." WebMD (8/2, Woznicki) also covered the study.

Postmenopausal women taking antidepressants may be at higher risk for stroke, death

Moral of the story: Postmenopausal women on antidepressants are 45% more likely than those not on such medication to have a stroke, and 32% more likely to die of any cause.

AMA Morning Rounds 12/15/09

Postmenopausal women taking antidepressants may be at higher risk for stroke, death.

The Los Angeles Times (12/14, Healy) "Booster Shots" blog reported that, according to a study published in the Archives of Internal Medicine, "postmenopausal women taking antidepressants are at higher risk of suffering a stroke or of dying of any cause than are those who do not take such medications." Investigators "followed 136,293 post-menopausal women, age 50 to 79, for just under six years," during which time "5,496 developed depression and were treated with antidepressant medication." Researchers found that over the course of "follow-up, the women on antidepressants were 45% more likely than those not on such medication to have a stroke, and 32% more likely to die of any cause."

        HealthDay (12/14, Edelson) reported that while the study found that "women on selective serotonin uptake inhibitors," such as "Celexa [citalopram], Paxil [paroxetine], Prozac [fluoxetine], and Zoloft [sertraline]," as well as "tricyclic antidepressants," had an increased risk for stroke and death, "the overall risk for any one woman remained very small."

Gingko biloba not effective in preventing cognitive decline, improving memory.

Moral of the story: Ginko is probably not worth buying for your mental health.

Source: AMA Morning Rounds 12/30/09; JAMA. 2009; 302:2663-2670

Gingko biloba not effective in preventing cognitive decline, improving memory.

The CBS Evening News (12/29, story 9, 0:20, Smith) reported, "Americans spend a quarter billion dollars a year on" gingko biloba supplements, "hoping to improve their memory and slow cognitive decline."

        NBC Nightly News (12/29, story 5, 2:00, Williams) reported that "now, a major study shows" that gingko biloba, "one of the most popular supplements, flat out does not work."

        USA Today (12/30, Weise) reports that, according to a study published in the Dec. 23-30 issue of the Journal of the American Medical Association, "the popular botanical...does not improve memory, nor does it prevent cognitive decline in older people." After analyzing data "from the Ginkgo Evaluation of Memory study" on "more than 3,000 people between ages 72 and 96 for seven years," researchers from the University of Virginia Medical School "found that a twice-daily dose of 120 milligrams of ginkgo biloba extract was not effective in reducing the incidence of Alzheimer's dementia or dementia overall."

        According to the Los Angeles Times (12/29, Kaplan) "Booster Shots" blog, the National Center for Complementary and Alternative Medicine, "a branch of the National Institutes of Health, has been researching ginkgo for 10 years to see whether the type of clinical trials required for FDA-regulated pharmaceuticals would reveal any benefit. The new findings are in line with several other studies, including a Cochrane review published this year that found 'no convincing evidence' that the herb preserves mental function in any way."

        The investigators "found no evidence that ginkgo delayed or prevented normal declines in memory, language, attention, visuospatial abilities, or executive functions, such as anticipating outcomes and adapting to changing situations and thinking abstractly," HealthDay (12/29, Reinberg) reported. Moreover, "these results remained the same regardless of sex, age, race or education," the investigators found. However, the supplement was found to be safe, "and no serious side effects were noted," study author Steven T. DeKosky, MD, said.

        WebMD (12/29, DeNoon) reported that "in a written statement," Douglas MacKay, ND, of the Council for Responsible Nutrition, "a group representing the supplement industry," said that "the DeKosky study 'should not be viewed as the final work' on ginkgo." He stated that "as a former practicing licensed naturopathic doctor," he "would continue to recommend ginkgo biloba to older adults as a safe, effective option for supporting cognitive health."

Ginkgo biloba for Preventing Cognitive Decline in Older Adults
A Randomized Trial
Beth E. Snitz, PhD; Ellen S. O’Meara, PhD; Michelle C. Carlson, PhD; Alice M. Arnold, PhD; Diane G. Ives, MPH; Stephen R. Rapp, PhD; Judith Saxton, PhD; Oscar L. Lopez, MD; Leslie O. Dunn, MPH; Kaycee M. Sink, MD; Steven T. DeKosky, MD; for the Ginkgo Evaluation of Memory (GEM) Study Investigators

JAMA. 2009;302(24):2663-2670.
Context  The herbal product Ginkgo biloba is taken frequently with the intention of improving cognitive health in aging. However, evidence from adequately powered clinical trials is lacking regarding its effect on long-term cognitive functioning.
Objective  To determine whether G biloba slows the rates of global or domain-specific cognitive decline in older adults.
Design, Setting, and Participants  The Ginkgo Evaluation of Memory (GEM) study, a randomized, double-blind, placebo-controlled clinical trial of 3069 community-dwelling participants aged 72 to 96 years, conducted in 6 academic medical centers in the United States between 2000 and 2008, with a median follow-up of 6.1 years.
Intervention  Twice-daily dose of 120-mg extract of G biloba (n = 1545) or identical-appearing placebo (n = 1524).
Main Outcome Measures  Rates of change over time in the Modified Mini-Mental State Examination (3MSE), in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and in neuropsychological domains of memory, attention, visual-spatial construction, language, and executive functions, based on sums of z scores of individual tests.
Results  Annual rates of decline in z scores did not differ between G biloba and placebo groups in any domains, including memory (0.043; 95% confidence interval [CI], 0.034-0.051 vs 0.041; 95% CI, 0.032-0.050), attention (0.043; 95% CI, 0.037-0.050 vs 0.048; 95% CI, 0.041-0.054), visuospatial abilities (0.107; 95% CI, 0.097-0.117 vs 0.118; 95% CI, 0.108-0.128), language (0.045; 95% CI, 0.037-0.054 vs 0.041; 95% CI, 0.033-0.048), and executive functions (0.092; 95% CI, 0.086-0.099 vs 0.089; 95% CI, 0.082-0.096). For the 3MSE and ADAS-Cog, rates of change varied by baseline cognitive status (mild cognitive impairment), but there were no differences in rates of change between treatment groups (for 3MSE, P = .71; for ADAS-Cog, P = .97). There was no significant effect modification of treatment on rate of decline by age, sex, race, education, APOE*E4 allele, or baseline mild cognitive impairment (P > .05).
Conclusion  Compared with placebo, the use of G biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment.
Trial Registration  clinicaltrials.gov Identifier: NCT00010803

Author Affiliations: Departments of Neurology (Drs Snitz, Saxton, Lopez, and DeKosky and Ms Dunn) and Epidemiology (Ms Ives), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Biostatistics, University of Washington, Seattle (Drs O’Meara and Arnold); Department of Mental Health, Johns Hopkins Medical Institutions, Baltimore, Maryland (Dr Carlson); Departments of Psychiatry and Behavioral Medicine (Dr Rapp) and Internal Medicine (Geriatrics/Gerontology), School of Medicine (Dr Sink), Wake Forest University, Winston-Salem, North Carolina; and School of Medicine, University of Virginia, Charlottesville (Dr DeKosky).

FDA warns against concomitant use of Plavix, certain heartburn drugs.

Moral of the story: If you are taking these two drugs (blood thinners and proton-pump inhibitors for heartburn) talk to your doctor. You need to up the dosage of the blood thinner.

Source: AMA Morning Rounds 11/18/09

FDA warns against concomitant use of Plavix, certain heartburn drugs.

NBC Nightly News (11/17, story 2, 0:40, Williams) reported that "millions of Americans take" Plavix (clopidogrel) "to reduce the risk of heart attacks and strokes." But, because the blood thinner "can upset the stomach, it is often prescribed alongside drugs like Prilosec (omeprazole) and Nexium (esomeprazole)." Now, however, the FDA is warning that those popular medications can "weaken the effect of Plavix."

In fact, the "anti-clotting benefits of Plavix are cut almost in half when taken with over-the-counter or prescription Prilosec, according to a notice posted today on the Food and Drug Administration's website," Bloomberg News (11/18, Larkin) reports. Thus, the "agency ordered Paris-based Sanofi and New York-based Bristol-Myers to update the prescribing information for Plavix and study the potential for other drug interactions." Although the "Plavix prescribing information was updated in January to discourage use with Prilosec," the latest warning includes the those two PPIs and nine other "similar drugs."

However, the agency "did not have enough information to say whether other drugs in the same class as Nexium and Prilosec...also react adversely with Plavix," the Los Angeles Times (11/18, Zajac) reports. "This includes such drugs as Prevacid [lansoprazole] and Protonix [pantoprazole]."

Nevertheless, those who still "need to reduce their acid should take drugs from the H-2 blocker family, which include Johnson & Johnson's Mylanta [aluminum hydroxide/magnesium hydroxide/simethicone] and Boehringer Ingelheim's Zantac [ranitidine]," the AP (11/18, Perrone) reports. "FDA scientists say there is no evidence those drugs interfere with Plavix's blood clotting." As for the omeprazole, the FDA decided to strengthen its warning after reviewing "a 150-patient study submitted by Sanofi over the summer."

That report indicated that drugs like Nexium reduce the production of an enzyme -- CYP 2C19 -- that sets Plavix in motion, according to the Wall Street Journal (11/18, Mundy). Several other drugs, WebMD (11/17, DeNoon) reported, "also inhibit CYP 2C19, and the FDA says patients on Plavix should avoid them as" well: Tagamet (cimetidine), Luvox (fluvoxamine), Ticlid (ticlopidine), Diflucan (fluconazole), Nizoral (ketoconazole), VFEND (voriconazole), Intelence (etravirine), Felbatol (felbamate), and Prozac, Serafem, and Symbyax (fluoxetine).

HealthDay (11/17, Reinberg), Dow Jones Newswire (11/17, Favole), and CQ HealthBeat (11/18) also covered the story

Spray-on anesthetic helps delay ejaculation.

Moral of the story: One of those awkward doorknob questions just got a better answer.

Source: AMA Morning Rounds 11/20/09

Bloomberg News (11/20, Matsuyama) reports, "A spray-on treatment for premature ejaculation may prolong sexual intercourse by as much as five times." In fact, the drug, known as PSD502, "delayed orgasm by an average of 108 seconds" after one month of treatment, according to a 256-patient trial conducted in Canada, Poland, and the US.

The work may benefit the estimated "one in three US men ages 18 to 59" who have dealt with the problem at one time or another, according to the Los Angeles Times (11/19, Maugh) "Booster Shots" blog. That's "about twice as many as those who suffer from erectile dysfunction." Indeed, "some antidepressant-like drugs, such as dapoxetine, have been approved in a few countries to treat the condition, but the Food and Drug Administration rejected it because of long-term side effects." And while "some physicians prescribe anesthetic creams like EMLA cream...off-label," they "require 45 minutes to work."

Now, researchers at the University of California-San Francisco may have stumbled upon a solution. According to WebMD (11/19, DeNoon), the spray "contains the anesthetics lidocaine and prilocaine," but it "doesn't deaden feeling, thanks to an ingredient in the spray that allows it to rapidly penetrate the skin." What's more, it "seems safe for men's female sex partners," as "only about 0.5% of female partners report decreased feeling in the vagina."

In light of those findings, HealthDay (11/19, Preidt) pointed out, "Sciele Pharma plans to seek US Food and Drug Administration approval of the spray." Reuters (11/20), the UK's Telegraph (11/19), and the UK's Press Association (11/19) also covered the story.

Depression and antidepressant use linked to sudden cardiac death

Moral of the story: You may want to stay on the antidepressants, but knowing your risks can help you to manage them. Being aware that you are at an increased risk for coronary heart disease means that you can better manage your other risk factors, and should try even harder to manage them. So get to work!

HeartWire - Arrhythmia/EP

Depression and antidepressant use linked to sudden cardiac death

March 9, 2009 | Lisa Nainggolan

New York, NY - A new analysis has found that major depression predicted cardiovascular morbidity and mortality in women participating in the Nurses' Health Study [1]. The hazard ratios were strongest for fatal events and were driven by the association of depression—in particular, antidepressant use—with sudden cardiac death (SCD). Dr William Whang (Columbia University, New York, NY) and colleagues report their findings in the March 17, 2009 issue of the Journal of the American College of Cardiology.

But the authors and accompanying editorialists conclude that, at the present time, the benefits of appropriately prescribed antidepressant use likely outweigh the risk of SCD.

"The absence of proof that antidepressants might cause cardiac events is more relevant than conclusive proof that this effect is absent. Nevertheless, these findings are sufficiently sobering to warrant heightened clinical surveillance and to initiate studies to definitively address this relationship," say Drs Sanjiv M Narayan and Murray B Stein (University of California, San Diego [UCSD]) in an accompanying editorial comment [2].

Whang told heartwire that he believes the biggest clinical implication of this new study "is that management of coronary heart disease risk factors may be especially important among women with depressive symptoms."

Those using antidepressants three times more likely to suffer SCD

Whang et al prospectively studied 63 469 women in the Nurses' Health Study without baseline coronary disease, stroke, or malignancy. They studied depressive symptoms and a proxy variable for clinical depression consisting of severe symptoms and/or antidepressant use and their relationship to cardiovascular events.

Questionnaires in 1992, 1996, and 2000 assessed depressive symptoms, with major depression defined by a validated five-point mental-health-index score (MHI-5) of <53,>

Of the women, 7.9% had MHI-5 scores of <53,>

From 1996 onward, the proxy variable of severe symptoms and/or antidepressant use was most associated with SCD in multivariable models (HR 2.33), and the risk was primarily due to a specific relationship between antidepressant use and SCD (HR 3.34).

Narayan and Stein say the work of Whang et al stands out from previous research of this kind: "[This research] is particularly exciting. The authors should be congratulated for these important data on the etiologic role of depression and its treatment on cardiovascular outcomes in a very large cohort of healthy individuals."

Arrhythmia a possible mechanism, but further study needed

"This surprising results merits scrutiny," the editorialists say. Numerous pharmaceutical agents might contribute to arrhythmic mortality, and in the present study, 61% of subjects were using selective serotonin-reuptake inhibitors (SSRIs), while 39% used other, nonspecified antidepressants.

"Our study raises questions about the mechanism by which depression is associated with sudden cardiac death," Whang told heartwire. "This is not the first study to link risk of SCD to depression. Our study is consistent with prior analyses that have found an association between depressive symptoms and a higher mortality in patients with CHD, and it points to arrhythmia as a possible mechanism for this worse prognosis."

Narayan and Stein say: "It is unclear whether SSRI agents might cause [sudden cardiac arrest]. While cardiac events are well documented with . . . tricyclic antidepressants, evidence for a link with SSRIs is mixed."

"Moreover, it is quite possible that antidepressant use merely indicates that depression is of sufficient severity to merit treatment." It is well established that patients with depression after acute coronary syndrome, for example, are less likely to adhere to their cardiac medication regimens, note the UCSD doctors, although treating the depression improves adherence.

"Clearly, the burden of proof rests on confirming this association. There are abundant data attesting to the safety and efficacy of SSRIs in particular, and a relative paucity showing adverse cardiac effects," they conclude.

Whang et al agree: "Although antidepressant medication use might be a marker of worse depression, its specific association with elevated risk of SCD merits further study."

Twin study shows depression itself independently associated with heart disease Chicago, IL - Separately, new research suggests that depression itself remains a significant contributor to incident heart disease after genetics and environmental, mental, and physical factors are controlled for [3]. The study, performed in 1200 male twins who served in the US military during the Vietnam War, was reported by Dr Jeffrey F Scherrer (Washington University School of Medicine and St Louis Veterans Affairs Medical Center) at the American Psychosomatic Society meeting last week "In this study, we have demonstrated that exposure to depression is contributing to heart disease only in twins who have high genetic risk and who actually develop clinical depression," says Scherrer in a Washington University School of Medicine statement. "In twins with high genetic risk common to depression and heart disease but who never develop depression itself, there was no increased risk for heart disease. The findings strongly suggest that depression itself independently contributes to risk for heart disease," he notes.

Narayan reports receiving speaking honoraria or serving as a consultant for St Jude Medical, Boston Scientific, Medtronic, Biosense-Webster, and Cambridge Heart. Stein receives or has received in the past three years research support from Eli Lilly and GlaxoSmithKline and is currently or in the past three years has been a consultant for BrainCells, Bristol-Myers Squibb, Eli Lilly, EPI-Q, Forest Laboratories, Hoffman La-Roche Pharmaceuticals, Integral Health Decisions, Jazz Pharmaceuticals, Johnson & Johnson, Mindsite, Pfizer, Sanofi-Aventis, Sepracor, Transcept Pharmaceuticals, and Virtual Reality Medical Center.

Sources

1. Whang W, Kubzansky LD, Kawachi I, et al. Depression and risk of sudden cardiac death and coronary heart disease in women. Results from the Nurses' Health Study. J Am Coll Cardiol 2009; 53:950-958
2. Narayan SM and Stein MB. Do depression or antidepressants increase cardiovascular mortality? The absence of proof might be more important than the proof of absence. J Am Coll Cardiol 2009; 53:959-961
3. Dryden J. Depression increases risk for heart disease more than genetics or environment [press release]. March 3, 2009. Available at: http://mednews.wustl.edu/news/page/normal/13643.html?emailID=23300.

Task force revises aspirin guidelines for heart attack, stroke

Moral of the story: Men between 45 and 79 should likely be taking asprin while women between 55 and 79 should likely be taking apsrin to prevent stroke. Talk to your physician about risk of GI bleeding. Thousands of lives could be saved by following these guidelines.

Task force revises aspirin guidelines for heart attack, stroke

Cardiovascular Business
Wednesday March 18, 2009

The U.S. Preventive Services Task Force has recommended aspirin use for primary prevention of heart attack and stroke in the March 17 issue of the Annals of Internal Medicine, citing its improved specificity over previous guidelines.

The task force found that men between the ages of 45 and 79 should use aspirin to reduce their risk for heart attacks when the benefits outweigh the harms for potential gastrointestinal bleeding. Women between the ages of 55 and 79 should use aspirin to reduce their risk for ischemic stroke when the benefits outweigh the harms for potential gastrointestinal bleeding.

However, the task force was against the use of aspirin for stroke prevention in women younger than 55 years and for MI prevention in men younger than 45 years.

"The task force has taken positive steps to lend clarity to patients and physicians about the value of aspirin for prevention of cardiovascular events," said American College of Preventive Medicine (ACPM) President Mark B. Johnson, MD. "The new guidelines make it clear that physicians, as a matter of routine practice, should be discussing the pros and cons of daily aspirin use with patients in the target groups."

An ACPM-sponsored survey published in the May 2007 edition of the American Journal of Preventive Medicine found a conversation between the patient and physician to be the strongest predictor of appropriate aspirin use, and that only about one in three patients who are at high risk are actually taking daily aspirin. A separate study by the Partnership for Prevention found that 45,000 lives could be saved each year if 90 percent of the target population took a low-dose aspirin every day. The studies led the American Medical Association (AMA) to adopt a policy to increase education among physicians on the importance of appropriate aspirin counseling.

With the release, the UPSTF updates its aspirin recommendations from 2002, which called on clinicians to discuss aspirin use for primary prevention with adults who are at increased risk for cardiovascular disease. The new USPSTF findings actually recommend aspirin use where benefits outweigh the harms, and further define the appropriate age and gender groupings for which aspirin is indicated.

"We think the new guidelines provide another tool in the armamentarium of the physician and the patient for assuring that a discussion about cardiovascular risk and potential aspirin use routinely takes place in the clinical setting," said David Shih, MD, senior director of medical affairs at ACPM.
Last Updated ( Thursday, March 19 2009 )

New Thinking on How to Protect the Heart

Moral of the Story: The Mediterranean diet really does work, as proven by a randomized clinical trial (the gold stardard of investigative medicine). The part about C-reactive protein is a bit misleading and I would disagree with Dr. Ozner about getting tested for it. CRP is an indicator but by itself has no effect on heart health. Since you should be following these guidelines anyway there would be no benefit to getting your CRP tested. However, if you are not following the guidelines and you need motivation, get it tested. Otherwise, enjoy some nice fish with veggies cooked in olive oil and you should be good to go.

NY TIMES ARTICLE: http://www.nytimes.com/2009/01/13/health/13brod.html?em

By JANE E. BRODY
Published: January 12, 2009
If last week’s column convinced you that surgery may not be the best way to avoid a heart attack or sudden cardiac death, the next step is finding out what can work as well or better to protect your heart.
Many measures are probably familiar: not smoking, controlling cholesterol and blood pressure, exercising regularly and staying at a healthy weight. But some newer suggestions may surprise you.
It is not that the old advice, like eating a low-fat diet or exercising vigorously, was bad advice; it was based on the best available evidence of the time and can still be very helpful. But as researchers unravel the biochemical reasons for most heart attacks, the advice for avoiding them is changing.
And, you’ll be happy to know, the new suggestions for both diet and exercise are less rigid. The food is tasty, easy to prepare and relatively inexpensive, and you don’t have to sweat for an hour a day to reap the benefits of exercise.
The well-established risk factors for heart disease remain intact: high cholesterol, high blood pressure, smoking, diabetes, abdominal obesity and sedentary living. But behind them a relatively new factor has emerged that may be even more important as a cause of heart attacks than, say, high blood levels of artery-damaging cholesterol.
That factor is C-reactive protein, or CRP, a blood-borne marker of inflammation that, along with coagulation factors, is now increasingly recognized as the driving force behind clots that block blood flow to the heart. Yet patients are rarely tested for CRP, even if they already have heart problems.
Even in people with normal cholesterol, if CRP is elevated, the risk of heart attack is too, said Dr. Michael Ozner, medical director of the Cardiovascular Prevention Institute of South Florida. He thinks that when people have their cholesterol checked, they should also be tested for high-sensitivity CRP.
Diet Revisited
The new dietary advice is actually based on a rather old finding that predates the mantra to eat a low-fat diet. In the Seven Countries Study started in 1958 and first published in 1970, Dr. Ancel Keys of the University of Minnesota and co-authors found that heart disease was rare in the Mediterranean and Asian regions where vegetables, grains, fruits, beans and fish were the dietary mainstays. But in countries like Finland and the United States where plates were typically filled with red meat, cheese and other foods rich in saturated fats, heart disease and cardiac deaths were epidemic.
The finding resulted in the well-known advice to reduce dietary fat and especially saturated fats (those that are firm at room temperature), and to replace these harmful fats with unsaturated ones like vegetable oils. What was missed at the time and has now become increasingly apparent is that the heart-healthy Mediterranean diet is not really low in fat, but its main sources of fat — olive oil and oily fish as well as nuts, seeds and certain vegetables — help to prevent heart disease by improving cholesterol ratios and reducing inflammation.
Virtues Confirmed
It was not until 1999 that the value of a traditional Mediterranean diet was confirmed, when the Lyon Diet Heart Study compared the effects of a Mediterranean-style diet with one that the American Heart Association recommended for patients who had survived a first heart attack.
The study found that within four years, the Mediterranean approach reduced the rates of heart disease recurrence and cardiac death by 50 to 70 percent when compared with the heart association diet.
Several subsequent studies have confirmed the virtues of the Mediterranean approach. For example, a study among more than 3,000 men and women in Greece, published in 2004 by Dr. Christina Chrysohoou of the University of Athens, found that adhering to a Mediterranean diet improved six markers of inflammation and coagulation, including CRP, white blood cell count and fibrinogen.
The same year Kim T. B. Knoops, a nutritionist at Wageningen University in the Netherlands, and co-authors published a study showing that among men and women ages 70 to 90, those who followed a Mediterranean diet and other healthful practices, like not smoking, had a 50 percent lower rate of deaths from heart disease and all causes.
“The Mediterranean diet is one people can stick to,” said Dr. Ozner, author of “The Miami Mediterranean Diet” and “The Great American Heart Hoax” (BenBella, 2008). “The food is delicious, and the ingredients can be found in any grocery store.
“You should make most of the food yourself,” Dr. Ozner added. “When the diet is stripped of lots of processed foods, you ratchet down inflammation. Among my patients, the compliance rate — those who adopt the diet and stick with it — is greater than 90 percent.”
Among foods that help to reduce the inflammatory marker CRP are cold-water fish like salmon, tuna and mackerel; flax seed; walnuts; and canola oil and margarine based on canola oil. Fish oil capsules are also effective. Dr. Ozner recommends cooking with canola oil and using more expensive and aromatic olive oil for salads.
Other aspects of the Mediterranean diet — vegetables, fruits and red wine (or purple grape juice) — are helpful as well. Their antioxidant properties help prevent the formation of artery-damaging LDL cholesterol.
Other Steps
Several recent studies have linked periodontal disease to an increased risk of heart disease, most likely because gum disease causes low-grade chronic inflammation. So good dental hygiene, with regular periodontal cleanings, can help protect your heart as well as your teeth.
Reducing chronic stress is another important factor. The Interheart study, which examined the effects of stress in more than 27,000 people, found that stress more than doubled the risk of heart attacks.
Dr. Joel Okner, a cardiologist in Chicago, and Jeremy Clorfene, a cardiac psychologist, the authors of “The No Bull Book on Heart Disease” (Sterling, 2009), note that getting enough sleep improves the ability to manage stress.
Practicing the relaxation response once or twice a day by breathing deeply and rhythmically in a quiet place with eyes closed and muscles relaxed can help cool the hottest blood. Other techniques Dr. Ozner recommends include meditation, prayer, yoga, self-hypnosis, laughter, taking a midday nap, getting a dog or cat, taking up a hobby and exercising regularly.
He noted that in a 1996 study, just 15 minutes of exercise five days a week decreased the risk of cardiac death by 46 percent.
Even very brief bouts of exercise can be helpful. A British study published in the current American Journal of Clinical Nutrition found that accumulating short bouts — just three minutes each — of brisk walking for a total of 30 minutes a day improved several measures of cardiac risk as effectively as one continuous 30-minute session.
This is the second of two columns on cardiac care. Last week: The drawbacks to interventional cardiology.

Does It Matter How Hypertension Is Controlled?

Moral of the story: The ACCOMPLISH trial showed new outcomes data that is not consistent with previous data, where there were no differences in benefit received as long as the drop in blood pressure was equivalent. It can't hurt to follow the results of the new data, so I would go with that.

Does It Matter How Hypertension Is Controlled?
Aram V. Chobanian, M.D.

Hypertension is one of the most important risk factors for cardiovascular and renal diseases. Currently, approximately 73 million adults in the United States and approximately 1 billion adults worldwide have hypertension, and the prevalence is increasing.¹ Many clinical trials have examined the effects of antihypertensive drugs. Studies comparing the effects of antihypertensive medications with those of placebo have shown consistently that lowering blood pressure is associated with major reductions in the incidence of coronary events, strokes, and congestive heart failure.² These benefits have been observed irrespective of age, sex, severity of the hypertension, presence or absence of associated risk factors or concomitant diseases, or class of antihypertensive drug used. However, the results of trials comparing the effects of different antihypertensive drugs or drug regimens have not been as consistent.

The initial findings from a new drug comparison study, the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial (ClinicalTrials.gov number, NCT00170950 [ClinicalTrials.gov] ), are reported in this issue of the Journal.³ The ACCOMPLISH trial was a randomized, double-blind, industry-sponsored study involving subjects with hypertension that examined the effects on cardiovascular outcomes of treatment with the angiotensin-converting–enzyme (ACE) inhibitor benazepril combined with either the calcium-channel blocker amlodipine or the diuretic hydrochlorothiazide. Somewhat surprisingly, as compared with the benazepril–hydrochlorothiazide group, the group that was treated with benazepril and amlodipine had a relative risk reduction of approximately 20%, and an absolute risk reduction of 2.2%, in the primary end point, a composite of illness and death from cardiovascular causes. The secondary end point of death from cardiovascular causes and nonfatal myocardial infarction and stroke showed a similar benefit.

The ACCOMPLISH study population was at high risk for cardiovascular diseases. The average age at entry was 68 years, and participants with a history of ischemic heart disease, peripheral vascular disease, stroke, left ventricular hypertrophy, or diabetes (which was present in 60% of the subjects) were included. Because the study design did not include a drug washout period, data on pretreatment blood-pressure levels were unavailable. However, most subjects probably had relatively severe hypertension; at study entry, 38% were receiving three or more antihypertensive drugs, yet only 37% had blood-pressure levels less than 140/90 mm Hg.

Most previous comparison trials have failed to show significant differences in the primary outcomes as long as equivalent decreases in blood pressure were achieved with the different drug regimens. Selected examples include the Swedish Trial in Old Patients with Hypertension-2 (STOP-2) trial, a study that examined treatment with diuretics and beta-blockers as compared with treatment with ACE inhibitors and calcium-channel blockers in elderly subjects with hypertension⁴; the International Verapamil-Trandolapril Study (INVEST) (NCT00133692 [ClinicalTrials.gov] ), a trial in which a regimen of verapamil with or without trandolapril was compared with a regimen of atenolol with or without hydrochlorothiazide among patients with hypertension and coronary heart disease⁵; and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (NCT00000542 [ClinicalTrials.gov] ), which compared chlorthalidone, lisinopril, and amlodipine therapies.⁶ In none of these trials did the primary outcomes differ between regimens. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), which compared treatment with the combination of amlodipine and perindopril with treatment with the combination of atenolol and bendroflumethiazide, the primary outcome of fatal coronary heart disease and nonfatal myocardial infarction also did not differ significantly between the two treatment groups; the composite secondary outcomes, which included stroke, were less favorable in the atenolol–bendroflumethiazide group, which also had average blood-pressure levels that were approximately 3 mm Hg systolic and 2 mm Hg diastolic higher than those of subjects in the amlodipine–perindopril group.⁷ In contrast, in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study (NCT00338260 [ClinicalTrials.gov] ), the primary cardiovascular outcomes (particularly stroke) with treatment with the angiotensin-receptor blocker losartan were better than those with atenolol therapy, even though there were similar reductions in blood pressure in the two groups.⁸ In the Second Australian National Blood Pressure Study, ACE-inhibitor therapy was associated with a somewhat lower incidence of cardiovascular events than thiazide-based treatment, although the benefit was observed only in men.⁹

No previous outcome trial has compared treatment with a combination of an ACE inhibitor and a calcium-channel blocker with treatment with the combination of an ACE inhibitor and a thiazide-type diuretic. ALLHAT compared chlorthalidone therapy with amlodipine therapy, though not in combination with an ACE inhibitor. The chlorthalidone dose used in ALLHAT and the hydrochlorothiazide dose used in the ACCOMPLISH trial were both in a range of 12.5 to 25.0 mg per day. Chlorthalidone is estimated to have double the potency of hydrochlorothiazide and a much longer duration of effect in this dose range. A recent study used 24-hour ambulatory blood-pressure measurements to study the effects of chlorthalidone (25 mg per day) as compared with hydrochlorothiazide (50 mg per day).¹⁰ Although blood-pressure levels measured during the daytime in the clinician's office were similar, blood-pressure levels measured during the nighttime, and 24-hour average blood pressures, were considerably lower with chlorthalidone than with hydrochlorothiazide. The reported blood-pressure levels measured in the clinician's office in the ACCOMPLISH trial were also relatively similar in the two treatment groups, but the possibility exists that the relatively low dose of hydrochlorothiazide used (averaging 19 mg per day) did not provide 24-hour blood-pressure control that was as effective as that provided by the benazepril–amlodipine regimen. Ambulatory blood-pressure measurements were apparently included in the design of the ACCOMPLISH trial,¹¹ and the data, if available, could address this issue in the future.

Experimental evidence has suggested that ACE inhibitors and calcium-channel blockers can have vasoprotective effects. These agents have been shown to inhibit atherosclerosis in various animal models with hypercholesterolemia and to improve endothelium-dependent vasodilatation in isolated arteries and in patients with vascular disease.^12,13 Diuretics do not share these properties. However, the clinical relevance of these findings is uncertain.

Are the results from the ACCOMPLISH trial applicable to the general population with hypertension? As noted above, the study participants were older and had relatively severe hypertension and a high prevalence of cardiovascular disease and diabetes. Although this group of subjects clearly does not mirror the broader population with hypertension, the same criticism can be applied to the other trials as well. Treatment recommendations should be based on the total available evidence rather than on the results of any single trial.

The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, published in 2003, included a strong preference for thiazide-type diuretics as the initial therapy for most patients with hypertension in the absence of compelling indications for specific drugs.¹⁴ However, it is time to reexamine these recommendations. The results from the many recent studies, including the ACCOMPLISH trial, when considered together, suggest that greater flexibility is now indicated in the choice of the initial drug. In my opinion, each of the major classes (diuretics, ACE inhibitors, calcium-channel blockers, angiotensin-receptor blockers, and, to a lesser extent, beta-blockers) appears reasonable as first-line therapy. The choice of a drug should depend on criteria such as compelling indications or contraindications, coexisting conditions, adverse effects, race, and the clinician's experience. Nevertheless, increased flexibility in choice should not negate the importance of diuretics, which have been a cornerstone of antihypertensive therapy for the past 50 years. The data from the ACCOMPLISH trial also should not diminish the value of treatment with the combination of an ACE inhibitor and a diuretic, a combination that effectively lowers blood pressure and that was recently shown to produce major reductions in mortality and morbidity in the very old.¹⁵

Many excellent medications are available to control hypertension. These drugs have acceptable side-effect and adverse-event profiles, and many are now available in generic versions, making cost less of an issue in the selection of a drug. Most patients with hypertension will require two or more drugs to control their hypertension, and combination drug formulations may also be useful. Although specific benefits may be provided by a given drug or drug combination, the evidence is overwhelming that the most important aspect of treatment is to reduce blood pressure to goal levels. How this is achieved is less important. Unfortunately, despite the remarkable progress in therapy, blood pressure remains inadequately controlled in almost two thirds of patients with hypertension in the United States. We must do better.

Dr. Chobanian reports serving as chair for the seventh report of the Joint National Committee, which developed guidelines for the management of hypertension, and receiving a lecture fee from Bristol-Myers Squibb of Mexico. No other potential conflict of interest relevant to this article was reported.

Source Information

From the Department of Medicine, Boston University School of Medicine, and the Boston University Medical Center, Boston.

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Benazepril plus Amlodipine or Hydrochlorothiazide for Hypertension in High-Risk Patients

Moral of the story: it matters what medications you are taking for high blood pressure. Talk to your physician about whether your regimen adheres to the recommendations of the ACCOMPLISH trial.

Benazepril plus Amlodipine or Hydrochlorothiazide for Hypertension in High-Risk Patients

Kenneth Jamerson, M.D., Michael A. Weber, M.D., George L. Bakris, M.D., Björn Dahlöf, M.D., Bertram Pitt, M.D., Victor Shi, M.D., Allen Hester, Ph.D., Jitendra Gupte, M.S., Marjorie Gatlin, M.D., Eric J. Velazquez, M.D., for the ACCOMPLISH Trial Investigators

ABSTRACT

Background The optimal combination drug therapy for hypertension is not established, although current U.S. guidelines recommend inclusion of a diuretic. We hypothesized that treatment with the combination of an angiotensin-converting–enzyme (ACE) inhibitor and a dihydropyridine calcium-channel blocker would be more effective in reducing the rate of cardiovascular events than treatment with an ACE inhibitor plus a thiazide diuretic.

Methods In a randomized, double-blind trial, we assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. The primary end point was the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization.

Results The baseline characteristics of the two groups were similar. The trial was terminated early after a mean follow-up of 36 months, when the boundary of the prespecified stopping rule was exceeded. Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril–amlodipine group and 132.5/74.4 mm Hg in the benazepril–hydrochlorothiazide group. There were 552 primary-outcome events in the benazepril–amlodipine group (9.6%) and 679 in the benazepril–hydrochlorothiazide group (11.8%), representing an absolute risk reduction with benazepril–amlodipine therapy of 2.2% and a relative risk reduction of 19.6% (hazard ratio, 0.80, 95% confidence interval [CI], 0.72 to 0.90; P<0.001).> of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke, the hazard ratio was 0.79 (95% CI, 0.67 to 0.92; P=0.002). Rates of adverse events were consistent with those observed from clinical experience with the study drugs.

Conclusions The benazepril–amlodipine combination was superior to the benazepril–hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events. (ClinicalTrials.gov number, NCT00170950 [ClinicalTrials.gov] .)