Emerging research on cardiovascular risk factors and treatment effects are helping clinicians gain a better understanding of which patients are most likely to benefit from close monitoring, lifestyle changes, and/or additional therapeutic interventions. New findings published in the March 30, 2010, Prevention and Outcomes Focus Issue of the Journal of the American College of Cardiology aim to evaluate the relationship between pre-diabetes and heart disease, determine the association between alcohol consumption and cardiovascular mortality, analyze the role of high-density lipoprotein cholesterol in reducing coronary heart disease, and examine how the use of clopidogrel can affect mortality.

Highlights from select studies published in the current issue of JACC find:

Light to moderate drinking linked to lower mortality in patients with cardiovascular disease

Moderate alcohol consumption for people with cardiovascular disease leads to a lower incidence of both cardiovascular and all-cause mortality, according to two meta-analyses recently conducted by Italian researchers. The findings extend to people with cardiovascular disease the same guidelines already determined for healthy people.

After searching for studies published through October 2009, the researchers selected 8 prospective studies that they used to draft two meta-analyses: one that examined alcohol intake and cardiovascular mortality and another that evaluated alcohol intake and all-cause mortality. Based on the experiences of 12,819 patients and 16,398 patients, respectively, both analyses found that maximal protection against mortality existed with consumption of 5 to 10 grams of alcohol per day. This protective effect remained significant up to 25 grams per day. Consuming more alcohol than 25 grams daily, however, led to higher mortality rates than abstainers, creating a J-shaped curve that showed both the “potential windows” of beneficial alcohol consumption and the “hazards of excessive drinking.”

The researchers conclude that cardiovascular patients can consume low-to-moderate amounts of alcohol—defined as 1 drink per day for women and up to 2 drinks per day for men—without harming their health (and while decreasing their mortality risk). They add that moderate alcohol consumption should be undertaken within the context of a healthy lifestyle, a good diet, and adequate drug therapy. However, the researchers note that patients who do not already regularly consume alcohol should not be encouraged to begin drinking.

Nationwide sample confirms connection of moderate alcohol intake and lower cardiovascular mortality

In a similar study conducted by U.S. researchers, light to moderate alcohol consumption was again associated with reduced cardiovascular death, while heavy drinking eliminated this risk reduction. According to the researchers, the study—which was conducted by analyzing 9 iterations of the CDC’s annual National Health Interview Survey (NHIS) between 1987 and 2000—provides “some of the strongest evidence to date” that the connection between moderate drinking and lower cardiovascular death can be generalized to the entire U.S. population. The NHIS is administered by the National Center for Health Statistics and the U.S. Bureau of the Census and includes a wide sample of the non-institutionalized U.S. population, with oversampling of selected minorities.

In addition to including a large, diverse study group, the researchers also sought to tackle one of the most difficult issues in alcohol epidemiology studies: whom to include in the abstainer cohort. Because former drinkers may have stopped due to health-related reasons, previous studies have found they have higher rates of mortality and thus may skew the results. In addition, critics have suggested that rare drinkers be excluded from the abstainer cohort or serve alternatively as the comparison group. In response to these issues, the researchers of the current study included 6 alcohol consumption categories: never drinkers, lifetime infrequent drinkers, and former drinkers, as well as light, moderate, and heavy current drinkers.

Among the 245,207 study participants, the researchers recorded a total of 10,670 cardiovascular deaths. They also found that light and moderate drinking were associated with a lower risk of cardiovascular mortality than the three abstainer cohorts, while heavy drinking was not significantly associated with higher or lower risk. Risk was similar among the never drinkers, lifetime infrequent drinkers, and former drinkers, suggesting that heightened concern about selecting the correct comparison group in alcohol studies may be unnecessary. After classifying the study participants into various subgroups (based on sex, race, age, and health status), the researchers saw that the association of light and moderate drinking with lower cardiovascular mortality remained for all subgroups.

Acknowledging the ongoing debate around alcohol studies, a physician from Kaiser Permanente Medical Center notes that the current study “adds to the case that the inverse relationship of light-moderate drinking to CV mortality is scientifically valid,” by using a national sample and by confirming that all three non-drinker cohorts had similar risk of CV death, thus reducing the likelihood of error by misclassification. He adds that while critics have emphasized methodological flaws that may heighten the apparent benefit of moderate drinking, less attention has been given to bias that may reduce benefit, such as confounding by smoking or underreporting of alcohol consumption by heavy drinkers. While he states that randomized, controlled trials would provide the most reliable outcomes, he notes that because of ethical issues, it is unlikely that one will be completed, and in its absence, physicians should use a “synthesis of common sense and the best available scientific facts” to determine optimal alcohol consumption for each patient.

High-density lipoprotein seen as promising target of current and future therapies for coronary heart disease

Studies have consistently shown an inverse association between high-density lipoprotein cholesterol (HDL-C) levels and the risk of coronary heart disease, which has led to increased interest in HDL-C as a therapeutic agent. Noting this fact, researchers conducted a review of HDL-C’s protective mechanisms and the therapies that harness its beneficial properties.

While low-density lipoproteins promote plaque build-up in the heart’s arteries, HDL-C counteracts the process in a few different ways, including through reverse cholesterol transport (moving excess cholesterol out of the body) and by inhibiting white blood cells from entering the subendothelial space where they promote build-up.

Acknowledging the important biological role that HDL-C plays in carrying out these mechanisms, the researchers report on various therapies designed to increase its production. They note that niacin (vitamin B3) is currently the “most effective pharmacologic means to raise HDL-C levels,” with levels generally raising 15 percent to 35 percent through its use. Niacin in combination use—with fibrates and statins—has also shown positive results and upcoming trials are further evaluating its safety and efficacy. Independent use of both statins and fibrates can also raise HDL-C levels, although these drug classes have only shown “modest” increases, according to the authors, at 5 percent to 15 percent and 10 percent to 15 percent, respectively. The authors note that the newer CETP inhibitors, apolipoprotein A-1 mimetics, and apolipoprotein A-1 upregulators “hold much promise,” because they target specific biological pathways involved in HDL-C metabolism and have more potent effects. One of the CETP inhibitors—anacetrapib— has shown to increase HDL-C levels by more than 130 percent. Looking to the future, the authors suggest that researchers will likely uncover important information in the next five years as to whether pharmacologic therapies should target certain subclasses of HDL-C and whether the flux or cycling of HDL-C is more important than absolute levels.

Although pharmacological interventions are effective, the authors also highlight lifestyle factors that can increase HDL-C levels, such as aerobic exercise, smoking cessation, moderate alcohol intake, and diet. They conclude that while pharmacologic treatment holds much promise in the near future, the current approach to affecting HDL-C levels is through these readily available lifestyle interventions.

Use of clopidogrel linked to lower mortality in patients with heart failure and heart attack who do not undergo angioplasty

Patients with heart failure and heart attack who do not undergo angioplasty have lower rates of death when given clopidogrel compared to patients not administered the drug, according to a Danish register study of 31,251 patients hospitalized between 2000 and 2005. The study is the first to examine the effect of clopidogrel on mortality in this specific high-risk patient population and may provide direction to clinicians who currently lack evidence-based guidelines for their treatment.

Clopidogrel—an oral antiplatelet drug used to prevent blood clots—is indicated alongside aspirin in all patients with heart attack except those with an increased risk of bleeding. Despite these guidelines, however, no analyses have been done specifically on acute heart attack patients with heart failure, leaving physicians uncertain how to best treat these patients. Seeking to address this issue, the researchers pulled data from the Danish National Patient Register to create four patient cohorts: two groups with heart failure (one receiving clopidogrel and one that did not) and two groups without heart failure (one receiving clopidogrel and one that did not). They then analyzed the outcomes from a mean follow-up period of 1.5 years for both heart failure groups and 2.05 years for both non-heart failure groups.

The researchers found that for patients with heart failure, 812 (32.2 percent) died in the group that was not treated with clopidogrel, compared to 709 (28.1 percent) from the group that received the drug (p = 0.002), creating a statistically significant difference. Comparatively, in the group without heart failure, 294 patients (9.7 percent) died without clopidogrel treatment, compared to 285 (9.4 percent) patients who received clopidogrel, an insignificant difference.

According to the researchers, former studies have shown low use of clopidogrel in patients with heart attack and heart failure who do not undergo angioplasty, which increases the importance of the main study finding that the drug reduces mortality in this patient population. They conclude that increased awareness of clopidogrel’s benefits in such high-risk patients could have “considerable clinical impact.”

In an accompanying editorial, a researcher from the HeartDrug Research Laboratories at Johns Hopkins University notes that because the value of using clopidogrel for heart failure patients has been “long debated,” the positive impact of the drug seen in the current study is “of unquestionable practical importance.” He adds that the positive outcome seen in a relatively short follow-up suggests potentially even better long-term survival. However, he does highlight a few issues with the study design, including certain clinical characteristics that were not included in the registry and other variables—such as drug compliance and side effects—that were not controlled for, and states that a head-to-head randomized study of conventional heart failure therapy with and without clopidogrel “is needed urgently.” 

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About the ACC:
The American College of Cardiology is leading the way to optimal cardiovascular care and disease prevention. The College is a 37,000-member nonprofit medical society and bestows the credential Fellow of the American College of Cardiology upon physicians who meet its stringent qualifications. The College is a leader in the formulation of health policy, standards and guidelines, and is a staunch supporter of cardiovascular research. The ACC provides professional education and operates national registries for the measurement and improvement of quality care. More information about the association is available online atwww.acc.org .