For Immediate Release January 12, 2009

Target Health is pleased to announce the appointment of Mark L. Horn, MD, MPH as Sr. Medical Director. Dr. Horn is a Board Certified Rheumatologist with over 20 years of experience in the Pharmaceutical Industry. At Pfizer, Inc., Mark oversaw development programs in multiple clinical disciplines, among them arthritis & inflammation, as well as cardiovascular, neurologic, and infectious diseases. In addition, he led teams in Licensing & Development and Medical Marketing. Most recently, Mark was leader of the Worldwide Medical Policy and Evidence Based Medicine/Health Technology Assessment Teams. These groups were responsible for analyzing trends and crafting strategies to address the increasingly complex, cost driven global requirements for clinical and economic data to justify reimbursement of prescription medicines by public and private payers. An additional major responsibility was developing strategies to respond effectively to the broad array of potential health reform initiatives in the United States. Mark is on the clinical faculty of the Mount Sinai Hospital and School of Medicine (NYC), is a current member of the US Pharmacopoeia Safe Medication Use Expert Committee. He also served on the US Pharmacopoeia Medicare Model Guidelines Expert Committee which, by Congressional statute, determined the categories and classes of medicines reimbursable under the Medicare Part D drug benefit. In addition to his MD (New York University) and undergraduate (Brown) degrees, Mark holds an MPH degree in Health Policy and Management (Columbia).

U.S. Department of Health and Human Services NATIONAL INSTITUTES OF HEALTH

NIH News National Institute on Aging (NIA) For

Immediate Release: Friday, January 16, 2009

Almost everyone knows about winter dangers such as broken bones from falls

on icy steps, sidewalks or streets. But cold weather also can cause an

important, less obvious danger that can affect older people. Older adults

are especially vulnerable to hypothermia, which can be deadly if not treated

quickly. The National Institute on Aging (NIA), part of the National

Institutes of Health (NIH), has some advice to help older people avoid hypothermia.

Hypothermia occurs when a person’s body temperature drops below normal and

stays low for a prolonged period of time. With advancing age, the body’s ability to endure long periods of exposure to cold is lowered.

Older people also are at risk for hypothermia because their body’s response

to cold can be diminished by certain illnesses such as diabetes and some

medicines, including over-the-counter cold remedies. In addition, older

adults may be less active and generate less body heat. As a result, they can

develop hypothermia even after exposure to relatively mild cold weather or a

small drop in temperature.

The best way to identify someone with hypothermia is to look for confusion

or sleepiness, slowed or slurred speech, shivering or stiffness in the arms

and legs, weak pulse or low blood pressure, poor control over body movements

or slow reactions. If you suspect that someone is suffering from the cold

and you have a thermometer available, take his or her temperature. If it’s

96 degrees or lower, call 911 for emergency help.

The NIA has information to help you prevent hypothermia. Here are a few


— Wear several layers of loose clothing when it is cold. The layers will

trap warm air between them. Tight clothing can keep blood from flowing

freely and lead to loss of body heat.

— Wear a hat, scarf, gloves or mittens, and warm clothes when you go

outside in cold weather. A significant amount of your body heat can be lost

through your head, and hands and feet are the first body parts to get cold.

— To keep warm at home, wear long underwear under your clothes, along with

socks and slippers. Use a blanket or afghan to keep legs and shoulders warm

and wear a hat or cap indoors.

— Make sure your home is warm enough. Set your thermostat to at least 68

to 70 degrees. Even mildly cool homes with temperatures from 60 to 65

degrees can trigger hypothermia in older people.

— Check with your doctor to see if any medications (prescription or over

the counter) you are taking may increase your risk for hypothermia.

Because heating costs are high, the U.S. Department of Health and Human

Services has funds to help low-income families pay their heating bills.

For more information, contact the Low Income Home Energy Assistance Program

(1-866-674-6327) or the Eldercare Locator (1-800-677-1116).

The NIA has free information about hypothermia. To order the fact sheet,

Hypothermia: A Cold Weather Hazard, or the brochure, Stay Safe in Cold

Weather, call toll free 1-800-222-2225. Hipotermia: El Peligro de las Bajas

Temperaturas is also available. These and other free publications on healthy

aging can be downloaded from the NIA Web site at .

The NIA leads the federal effort supporting and conducting research on aging

and the medical, social and behavioral issues of older people. For more

information on research and aging, go to .

The National Institutes of Health (NIH) — The Nation’s Medical Research

Agency — includes 27 Institutes and Centers and is a component of the U.S.

Department of Health and Human Services. It is the primary federal agency

for conducting and supporting basic, clinical and translational medical

research, and it investigates the causes, treatments, and cures for both

common and rare diseases. For more information about NIH and its programs,

visit .

This NIH News Release is available online at:


Peter Libby, chief of cardiology at Brigham and Women’s Hospital, explains what C-reactive protein, one focus of the JUPITER study, may have to do with heart disease

Photo by Brykmantra via Flickr

By Peter Libby MD — In deciding whether a patient requires therapy to prevent an atherosclerosis-related heart attack or stroke, physicians usually rely heavily on measurements of cholesterol in the person’s blood. But that approach misses a great many vulnerable individuals. Several studies suggest that measuring blood concentrations of C-reactive protein – or CRP, a marker of inflammation – could add useful information. Indeed, in one recent report, Paul M. Ridker of Brigham and Women’s Hospital demonstrated that examining both CRP levels (which cannot be predicted from cholesterol measures) and cholesterol levels provides a more accurate indication of risk than assessing cholesterol alone.

Ridker grouped cholesterol levels in the general adult population into five progressively rising ranges (quintiles) and, separately, divided CRP levels into quintiles as well. Then he determined the relative risk faced by people having different combinations of cholesterol and CRP values. That is, he assigned a danger level of “one” to individuals whose cholesterol and CRP values both fell in the lowest quintile (front corner) and calculated how much that risk multiplied in adults having other permutations of cholesterol and CRP measurements.

He found that high CRP values signify markedly elevated risk for heart attack or stroke even in individuals with seemingly reassuring cholesterol values. For instance, people with average (third-quintile) cholesterol levels and the highest CRP levels face much the same peril as those who have the highest cholesterol and lowest CRP levels. And subjects having the highest values for both cholesterol and CRP confronted the greatest risk of all. Encouraged by such results, researchers now hope to undertake a large study assessing whether basing such treatment decisions on combined CRP and cholesterol testing will save lives.

By Jonathan D. Edwards, PharmD, Edward H. Eiland III, PharmD, MBA,BCPS, CGP

Currently, sepsis–a systemic inflammatory response syndrome initiated secondary to an infection–is the tenth leading cause of death in the United States.1 Approximately 750,000 patients develop sepsis each year.2,3 Sepsis-related mortality ranges from 30% to 50%, with advancing age increasing the risk.4,5 Two factors that contribute to a positive outcome in the treatment of sepsis are the timely diagnosis and identification of the offending pathogen. The four cornerstones of the therapeutic management of sepsis are hemodynamic monitoring, volume resuscitation, inotropic therapy, and red blood cell transfusions. Despite therapeutic advances, sepsis-related morbidity and mortality continue to increase.3

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are an integral part of the medication armamentarium for treating hyperlipidemia and reducing the risk of coronary artery disease. Their beneficial effects are due to statins’ ability to inhibit the rate-limiting step of cholesterol biosynthesis, thereby decreasing the amount of circulating cholesterol in the body (FIGURE 1).6 These well-documented benefits are termed lipid-dependent effects. It has recently been discovered that statins possess effects beyond their lipid-lowering properties; these are termed lipid-independent or pleiotropic effects. Pleiotropic effects include anti-inflammatory, immunomodulatory, antioxidant, antithrombotic, and endothelium-stabilizing properties. Patients with sepsis syndrome experience dysfunction in all of these areas; therefore, statins theoretically would benefit them.6 The overall clinical impact of statins for treating sepsis is not fully delineated, however.


Rationale for Sepsis Improvement After Statin Use

Cytokines 6,7: Sepsis activates an inflammatory cascade in which large amounts of cytokines are released into the body. Macrophages and endothelial cells are then hyperactivated by the unusually large quantity of circulating cytokines. The activation of macrophages and endothelial cells results in the release of more cytokines, exacerbating the inflammatory response. Statins have the ability to alter the expression of various cytokines (FIGURE 2). This alteration may lead to a reduction in the release of cytokines, thus breaking the chain between cytokine release and activation of macrophages and endothelial cells. These events potentially could culminate in the blunting of the inflammatory component associated with sepsis syndrome.


C-Reactive Protein6,7 : C-reactive protein (CRP) is a nonspecific marker for inflammation in the body. Increased CRP levels have been associated with deleterious clinical outcomes. CRP, which is produced by the liver, is driven by the release of cytokines. As previously mentioned, sepsis precipitates an augmented chain of events that ultimately results in the release of a large amount of cytokines. CRP assists with endothelial-cell interaction, aids in the activation of complement, and induces tissue-factor expression. These actions work in concert to promote the formation of thrombi. Statins have the ability to deter cytokine release, thus leading to decreased amounts available to the liver for producing CRP. In theory, this action would reduce systemic inflammation and improve clinical outcomes in the septic patient.

Chemokines6,7: Chemokines attract leukocytes to sites of infection or tissue damage. Statins have been shown to bind directly to the lymphocyte’s cell surface, which prevents binding to the counterreceptor on the endothelial surface (FIGURE 3). Statins also reduce the production of chemoattractants. These actions result in a net decrease of inflammatory cells in the body. Statins also exert favorable effects on T lymphocytes. The Th-1 subclass of T lymphocytes promotes inflammation, which is inhibited by statins; the Th-2 subclass promotes anti-inflammation, which is expressed by statins (FIGURE 2). Therefore, statins are able to alter T lymphocytes, thereby halting an inflammatory effect and inducing a net anti-inflammatory effect.

Coagulation6,7 : Sepsis-induced inflammation causes the downregulation of thrombomodulin and the upregulation of tissue factor on the surface of the endothelium. This shift results in endothelial dysfunction and favors thrombosis. Statins increase thrombomodulin on the endothelial surface and reduce tissue-factor expression in endothelial cells. This action has the potential to reduce the generation of thrombin. The increased amount of thrombomodulin on the surface of the endothelium allows it to be readily available to bind with thrombin. The net result of this binding is the activation of protein C. This activation will result in the initiation of the intrinsic anticoagulant cascade. Therefore, statins have the theoretical ability to blunt or reverse the procoagulant state that exists in sepsis syndrome (FIGURE 2).


Enzymes6,7: Sepsis causes an increase in inducible nitric oxide (NO) synthase (NOS), which leads to the overproduction of NO. This overproduction leads to excessive vasodilatation, loss of systemic vascular resistance, and vascular leak. Statins modulate NOS activity and, consequently, NO levels by reducing inducible NOS expression and by maintaining or increasing endothelial constitutive NOS production. This reduction in the inducible NOS/endothelial constitutive NOS ratio may be clinically important since unselected NOS blockade is associated with increased mortality (FIGURE 2).

Antioxidant Effects 6,7: Reactive oxygen levels are increased in patients with sepsis. It has been reported that oxidative stress is an important factor associated with morbidity and mortality in patients with sepsis and multisystem organ failure. Statins inhibit phorbol myristate acetateñinduced oxygen radical production in monocytes through NADPH oxidase inactivation. Activation of this enzyme is largely responsible for the production of reactive oxygen species in sepsis ( FIGURE 2).

Studies Addressing Statin Therapy and Sepsis

Liappis et al conducted a single-center, retrospective, cohort trial to compare mortality and clinical findings in patients taking statins with those of patients not receiving statins at the time of their bacteremic episode.8 Of the 388 subjects, 35 were taking a statin; the rest (n = 353) were not. The authors found a significant reduction in overall hospital mortality rates among patients taking statins, with a mortality rate of 6% in the statin group and a rate of 28% in the nonstatin group. Mortality rates that could be attributed to the infection were lower in the statin group (3%) than in the nonstatin group (20%). The authors concluded that statins might prove beneficial in the treatment of infections, but that prospective studies were needed to validate this potential benefit. This trial had several weaknesses, including a small number of subjects in the statin group, unbalanced baseline characteristics, and a questionable study design.

The association between statin administration and mortality in bacteremic patients requiring hospital admission was assessed by Kruger et al in a single-center, retrospective, cohort trial.9 This study involved 438 patients, 66 of whom were receiving statin therapy upon admission (the remaining 372 were not). Compared with the group that did not receive statins, the statin group had a significantly lower incidence of hospital mortality (10.6% versus 23.1%) and bacteremia-related mortality (6.1% versus 18.3%). There also was a reduction in all-cause hospital mortality (1.8% versus 23.1%) and in death related to bacteremia (1.8 versus 18.3%), which was more pronounced in patients who continued to receive statin therapy after the diagnosis of bacteremia. The authors concluded that statin administration provided a significant survival benefit and recommended that more trials be conducted to evaluate statin utilization in critically ill patients. Two weaknesses of this trial were the small number of patients in the statin group and the inability to extrapolate to a larger patient population.

Fernandez et al conducted a single-center, retrospective, cohort trial of 438 subjects to assess the impact of previous statin therapy on hospital mortality and determine whether the impact is due to a protective effect against ICU-acquired infections. 10 Prior to ICU admission, 38 subjects were receiving statin therapy and the remaining 400 were not. This trial found no difference with respect to ICU-acquired infections between subjects who were taking statins preadmission and those who were not receiving statin therapy. Paradoxically, there was a higher rate of mortality in the statin group. The authors concluded that the higher occurrence of mortality in the statin group might have been related to the greater severity of illness in that group. The authors also suggested the need for prospective, randomized trials in order to validate their findings. Weaknesses of this trial were generalized inclusion criteria, no reason listed for ICU admission, and differences in baseline characteristics between the two groups that may have led to skewed results.

A single-center, prospective, observational, cohort study undertaken by Almog et al evaluated whether patients treated with statins developed severe sepsis less frequently and whether this presumed protective effect might reduce the rate of admission to the ICU.11 The study included 361 subjects, 82 of whom were receiving statin therapy prior to hospital admission; the rest (n = 279) were not receiving statin therapy. Severe sepsis developed in 2.4% of subjects receiving prior statin therapy and in 19% of those not receiving it–a statistical and clinical difference between the two groups. The subjects receiving statin therapy also had a significantly reduced incidence of ICU admission (3.7%) compared with the nonstatin group (12.2%). The investigators found that therapy with statins for at least one month before the onset of an acute bacterial infection is probably associated with a reduced rate of severe sepsis and ICU admission. They reiterated a need for future prospective, controlled trials to verify their results and to determine the clinical significance of statins as a preventative approach to sepsis. Weaknesses of this trial included unbalanced baseline characteristics, a relatively smaller statin group, and the study design.

A population-based, retrospective, cohort analysis was conducted by Thomsen et al to investigate statin use and mortality due to bacteremia.12 This trial involved 5,353 subjects, 176 who had received statin therapy and 5,177 who had not. Up to 30 days, mortality between the two groups was similar. However, between days 31 and 180, the statin group experienced a significantly lower incidence of mortality than the non-statin group. These results suggested that statins may not possess short-term benefits in the treatment of bacteremia, but may cause a reduction in long-term mortality. The researchers concluded that, due to the trial’s weaknesses, the benefits of statin therapy for bacteremia were difficult to interpret. Two weaknesses were the relatively small size of the statin group and the study design (observational).

Hackam et al engaged in a large, population-based, retrospective, cohort study of 69,168 patients that investigated the use of statins and their effect on sepsis.13 The statin group and the nonstatin group each comprised 34,584 patients. The authors found that the rate of sepsis was significantly lower in patients receiving statin therapy prior to hospital admission compared with patients not receiving statin therapy prior to admission. The design of this study was considered a weakness due to the possibility that confounding factors had been introduced.

A small, single-center, retrospective, cohort trial of 53 subjects was carried out by Martin et al. 14 Sixteen subjects were receiving statin therapy and 37 controls were not receiving statin therapy prior to admission. The trial investigated whether the use of statins is associated with a reduced rate of severe sepsis in a population of patients with confirmed sepsis; it also aimed to further characterize the effect of statins on the frequency of organ dysfunction in patients with severe sepsis. The authors established that statins were associated with a significantly lower instance of severe sepsis (56%, versus 86% for the nonstatin group). No difference in mortality was noted between the two groups (38% in the statin group and 49% in the non-statin group), however. The statin group had a significant reduction in the rate of cardiovascular dysfunction compared with controls (38% versus 73%). The authors concluded that statins may provide an interventional strategy in patients with severe sepsis or septic shock. They suggested further investigation in the form of randomized, prospective, placebo-controlled trials involving patients with sepsis. Weaknesses of this trial were its small sample size, analysis of a single center, and retrospective evaluation.

Yang et al conducted a retrospective study involving patients with sepsis.15 The objective was to define the effect of statins on 30-day mortality in an Asian population with sepsis. Of the 454 patients studied, 104 received a statin at least 30 days before hospital admission and during the course of the septic event. The other 350 patients were considered controls and did not receive statin therapy prior to admission. There was no significant difference in 30-day sepsis-related mortality between the two groups (19.2% versus 18.9%). The investigators concluded that there were no marked beneficial or harmful effects of statin therapy during sepsis in terms of 30-day survival rates of bloodstream infections in this population. Weaknesses of this trial were unbalanced baseline characteristics and restrictive inclusion criteria.


The pleiotropic effects associated with statin therapy are well documented and are gaining increased attention. Sepsis is associated with inflammatory processes, coagulopathies, oxidative stress, and vascular dysfunction. These deleterious effects theoretically could be modified by statin therapy, which leads to the assumption that statins may have beneficial effects in patients diagnosed with sepsis. However, due to weak methodology and conflicting results, current trials are unable to provide a definitive answer to this interesting question. The available literature does suggest a positive association between statin therapy and improved patient outcomes, but this must be validated by large, randomized, double-blind, controlled trials. Statins cannot presently be recommended as a therapeutic modality in the treatment or prevention of sepsis.


C-Reactive Protein- Helpful or Hype?


Princeton Longevity Center , January 15, 2009, by David A. Fein MD — Much attention has been focused in the media recently on the role of C-Reactive Protein as a predictor of cardiovascular risk. In this edition of our newsletter we explore whether the evidence has been over-blown or could this simple blood test truly predict who is at risk

C-Reactive Protein (CRP) is not a new addition to medical testing. It was first discovered in 1930 in patients with acute inflammation related to infection. CRP is a member of class of molecules commonly found in the blood known as Acute Phase Reactants. The levels of these substances increase dramatically as part of the inflammatory process, including in response to infections, some cancers and a wide variety of other less ominous conditions. CRP levels rise within hours of the start of inflammation and will return to normal within a day or two when the inflammatory stimulus is removed.

Inflammation is believed to play a role in the progression of atherosclerosis. Most importantly, inflammation may directly increase the risk of rupture of an atherosclerotic plaque already present in an artery. Plaque rupture leads to the formation of a blood clot, blocking off the blood flow in the artery and causing a heart attack or stroke.

As a marker of inflammation, CRP has shown some utility as a very mild predictor of cardiovascular risk. To measure cardiovascular risk, a “high sensitivity” CRP (hs-CRP) blood test must be done. Elevated levels, above 2.4 mg/l, have been associated in some studies with a doubling of the risk of a coronary event compared to levels below 1 mg/l. In the recently published JUPITER trial patients with elevated hs-CRP levels were given statin therapy (drugs that are commonly used to lower cholesterol) with Rosuvastatin. Statins are known to reduce inflammation and those patients who took Rosuvastatin in the study averaged a 37% decrease in their hs-CRP. The study found that those patients who had high levels of hs-CRP prior to treatment had a significant reduction in the number of cardiovascular events

So, does this mean that we should use hs-CRP as a marker for increased cardiac risk and start treating everyone with an elevated level?

As noted above, CRP levels can change very quickly and often vary from day to day. A single elevated hs-CRP is likely to be of little value. At the least, the test should be repeated several times to demonstrate that the hs-CRP remains consistently high.

The presence of visceral fat, the type of fat that occurs inside the abdomen around the internal organs as opposed to subcutaneous fat under the skin, is associated with increased levels of inflammation. Visceral fat typically accumulates in response to high carbohydrate diets, alcohol intake and insufficient exercise, among other causes. So, a change in diet, weight or exercise can cause hs-CRP levels to increase. Improving the lifestyle factors that underlie the change will bring the hs-CRP and inflammation back down. Simply having an elevated hs-CRP may not justify lifelong drug therapy when the problem may be correctable with lifestyle changes.

The bigger concern is that while inflammation is likely to play a role in both the progression of atherosclerosis and the risk of symptomatic cardiovascular events, we don’t know what role it plays in people who do not have pre-existing atherosclerosis. Studies published several years ago established that patients with plaque seen on a Heart Scan had an even higher risk of cardiac events if they also had an elevated hs-CRP. On the other hand, patients who did not have any detectable plaque on their Heart Scan had a very low risk of heart attack or stroke whether or not they had an elevated hs-CRP.

The JUPITER trial looked at all people with elevated hs-CRP but did not differentiate those who had atherosclerosis from those who didn’t. So, while a reduction in risk was seen on average across all those patients who had an elevated hs-CRP, it is very plausible that there was a very large risk reduction from treating those who have plaque while those who did not have plaque had no benefit at all.

In that case, using hs-CRP alone to determine who should be treated is very likely to result in a large number of people being treated who can not benefit because they don’t have atherosclerosis in the first place. The JUPITER trial authors estimated that 95 patients with elevated hs-CRP levels would need to be treated to prevent just 1 cardiac event over a 2 year period.

Therefore, our recommendation is that hs-CRP is not useful primarily as an initial screening tool as it does not differentiate those with high risk plaque from those without any plaque and a low risk. The initial screening step should be a Coronary Calcium Score to determine the total amount of plaque present. Those with zero scores and no detectable plaque do not need further risk stratification. Those with more than moderate amounts of plaque may benefit from measuring hs-CRP and instituting more aggressive and earlier treatment if the hs-CRP is elevated.

In patients who have already been found to have a high hs-CRP, a Coronary Calcium Score may help to differentiate those who need more aggressive treatment. If no detectable plaque is present then simple lifestyle changes, such as improved diet and exercise along with Omega 3 supplementation, should help to lower the levels of inflammation which may alter the long-term risk of eventually developing atheroscolerosis.