At the annual American College of Cardiology meeting in Chicago, from March 23 to 27, 2012, approximately 18,000 cardiologists and other health care professionals attended sessions that included presentations of positive findings for immediate-use glucose, insulin, and potassium (GIK); vorapaxar; and rivaroxaban. This article also reviews of toxicities and interactions that often put ill-informed users of dietary supplements at risk.
. 2012 May;37(5):303–305.
P T. 2012 May;37(5):303.
In prior clinical trials, GIK (glucose, insulin, and potassium) failed to show benefit, despite the fact that experimental studies have shown a wide range of benefits in cardiac ischemia. Those benefits have included improved glucose, glycogen, and energy metabolism; maintenance of cellular adenosine triphosphate (ATP) levels; support of cardiac function; delays in necrosis; decreased levels of plasma and cellular free fatty acids (which damage membranes, cause arrhythmias, and waste oxygen); and preservation of potassium in myocytes (which protects against arrhythmias).
In the experimental studies, GIK was started immediately and was followed by reperfusion. In the failed trials, GIK was given after reperfusion, about 6 hours later, during the course of an acute myocardial infarction (MI) or ST-segment elevation MI (STEMI). These trials, moreover, were not placebo-controlled.
The Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care (IMMEDIATE) trial was conducted by 36 emergency medical services (EMS) systems in 13 cities in the U.S. A total of 432 subjects were randomly assigned to receive GIK; 479 participants (mean age, 63.5 years) received placebo. Time from the onset of symptoms to administration of the study drug was 90 minutes for both the GIK and placebo groups.
In this trial, investigators were looking for evidence of GIK effects on progression to MI, ultimate size of the infarct, and prevention of arrhythmias and cardiac arrest. The EMS workers used a “predictive instrument decision support,” as printed on the electrocardiograph devices (ECGs), to help identify patients with acute coronary syndrome (ACS) and STEMI immediately. Qualifying patients received very early use of GIK (30% glucose plus 50 units of insulin plus 80 mEq of potassium chloride/L at 1.5 mL/kg per hour). After confirmation by emergency department physicians, this dose was continued in the hospital for a total of 12 hours.
Progression to MI occurred in 49% of subjects in the GIK group and in 52% of those in the placebo group (P = 0.28). Thirty-day mortality rates were 4% with GIK and 6% for placebo (P = 0.27). The endpoint of cardiac arrest or hospital mortality significantly favored GIK (4% and 6%, respectively, P = 0.01). Similar patterns were found for patients presenting with STEMI, again with a significant advantage for GIK in the endpoint of cardiac arrest or hospital mortality (6% GIK, 14% placebo; P = 0.01).
Further significant benefits for GIK, compared with placebo, were reported for 30-day infarct size and FFA levels. Glucose levels above 300 mg/dL, as expected, occurred significantly more often in GIK-treated patients with and without diabetes.
Rates of adverse effects with GIK were low, and the drug’s cost, Dr. Selker underscored, is low. He concluded that the risk of cardiac arrest or death was reduced by half in the IMMEDIATE trial among patients with ACS and STEMI when paramedics administered intravenous GIK as soon as possible.
P T. 2012 May;37(5):303–304.
Thrombolysis in Myocardial Infarction 50 (TIMI-50), a randomized, double-blind, multinational trial, tested aspirin and other standard antiplatelet agents plus placebo or plus more intensive antiplatelet therapy with Merck’s vorapaxar, an investigational selective protease-activated receptor (PAR-1) antagonist. The tested population had experienced previous myocardial infarctions (MIs) (n = 17,779), cardiovascular accidents (n = 4,883), or peripheral artery disease (n = 3,787). Patients were observed for more than 2 years.
Primary efficacy endpoints were cardiovascular (CV) death, MI, stroke, and hospitalization for ischemia; urgent coronary revascularization, CV death, MI, and stroke; and CV death or MI. Safety endpoints were moderate or severe bleeding, as defined in the Global Utilization of Streptokinase and T-PA for Occluded coronary arteries trial (GUSTO) and TIMI clinically significant bleeding. The subgroup with a history of stroke discontinued vorapaxar when the data safety and monitoring board noted an increase in intracranial hemorrhage with the drug.
At a median follow-up period of 2.5 years, the risk of CV death, MI, or stroke was reduced with vorapaxar, compared with placebo, by 13% and by 9.3% vs. 10.5%, respectively, at 3 years (P < 0.001). This reduction in new CV events appeared greatest in patients with a prior MI, some of whom experienced a 20% decline in recurrent events (P < 0.001).
At 3 years, GUSTO moderate or severe bleeding was reported in 4.2% of patients receiving vorapaxar and in 2.5% of patients receiving placebo (P < 0.001). Rates of intracranial hemorrhage were also higher with vorapaxar than with placebo (1.0% vs. 0.5%, respectively; P < 0.001). Rates of intracranial hemorrhage were lower in patients with no history of stroke (0.6% with vorapaxar vs. 0.4% with placebo; P = 0.049).
“Patient selection is necessary to balance the antithrombotic benefit versus risk of bleeding,” Dr. Morrow said.
“In very selected patients,” commented Dr. Holmes, “and in very selected, very good centers, this technology, this group of drugs [PAR-1 antagonists] offers the potential to improve outcomes, with an important safety hazard. It is not, however, for everybody.”
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Standard therapy for pulmonary embolism, which consisted of injections of enoxaparin (Lovenox, Sanofi), a low-molecular-weight heparin, followed by a vitamin K antagonist (either warfarin or acenocoumarol) given in the right way, Dr. Büller said, “is perfectly effective and reduces recurrent thrombosis by almost 90%.” The need for International Normalized Ratio (INR) monitoring and risks of interactions with antibiotics, alcohol, and some foods, however, make that standard therapy “a nightmare to give,” he added.
As an alternative therapy for pulmonary embolism (PE), the oral anticoagulant rivaroxaban (Xarelto, Bayer) was tested in EINSTEIN PE, a clinical trial conducted at 263 sites in 38 countries. Investigators randomly assigned 2,419 patients to receive rivaroxaban and 2,414 patients to receive standard treatment. All enrolled patients had a primary diagnosis of PE, and 25% in both groups also had deep vein thrombosis (DVT). Treatment duration, by clinician pre-randomization choice, was 3, 6, or 12 months.
The rivaroxaban group received 15 mg twice daily for 3 weeks, followed by 20 mg once daily. In the standard-therapy arm, the regimen of enoxaparin (1.0 mg/kg, twice daily) was continued for at least 5 days and stopped when the INR was 2.0 or higher for two consecutive days. A vitamin K antagonist was started within 48 hours after randomization, and the dose was adjusted to maintain an INR of 2.0 to 3.0. The primary efficacy outcome was a first symptomatic recurrence of venous thromboembolism (VTE). VTE includes both DVT and PE.
VTE was reported in 50 patients (2.1%) receiving rivaroxaban and in 44 patients (1.8%) in the standard-therapy arm (P = 0.0026 for non-inferiority of rivaroxaban). Recurrent DVT was reported in 0.7% of patients in both groups, and recurrent nonfatal PE was reported in 0.9% of patients who received rivaroxaban and in 0.8% receiving standard enoxaparin plus a vitamin K antagonist. Fatal or possible PE was reported in 0.4% and 0.2% of participants, respectively. At 3 years, major or non-major bleeding, the principal safety outcome, was similar in the two groups (10.3% for rivaroxaban and 11.4% for enoxaparin; P = 0.23). Major bleeding, however, occurred less often with rivaroxaban (1.1% vs. 2.2% for enoxaparin; P = 0.0032).
Most of the excess in major bleeding, Dr. Büller pointed out, occurred in patients older than 75 years of age. However, he said that the efficacy and safety results overall were consistent, irrespective of age, body weight, sex, kidney function, or the presence of cancer. No liver toxicities were evident.
Investigators also merged EINSTEIN PE data with data from an identically designed EINSTEIN DVT study, totaling more than 4,000 patients. In that analysis, the efficacy hazard ratio combined was 0.89, compared with standard therapy.
“This allows me to conclude that this regimen provides patients and clinicians with a simple, single drug treatment,” Dr. Büller said.
P T. 2012 May;37(5):304–305.
Who is using dietary supplements? What are they using? Why should we care?
The answers are “many, much, and often they contain medically consequential substances,” Dr. Cooper-DeHoff said; health care providers, therefore, do need to pay heed. The 100 million Americans who regularly consume dietary supplements tend to be women who are richer and more educated than the general population. They are also more likely to be Native American or Caucasian.
The $15 billion that consumers spend out of pocket represents a full one-third of what is spent out of pocket on prescription drugs. According to a 2006 AARP survey, these dollars are spent to treat a specific health condition (66%), to attain or maintain overall wellness (65%), to supplement conventional medicine (45%), or to prevent illness (42%).
Distinct trends in supplement use in the U.S., as documented by the top 10 natural products among adults noted in research comparing the years 2002 and 2007,1 include a reduction in Echinacea use and increases in use of fish oil, glucosamine, and flaxseed oil, with new uses of CoEnzyme Q10 (Co-Q10) and chondroitin emerging. The three categories of dietary supplements purchased most often were aimed at weight loss, energy enhancement, and sexual enhancement. Danger lies in the fact that individuals taking them assume that because they are natural, they are safe.
Caffeine-laden weight-loss products can lead to tachycardia and hypertension. As with energy drinks and total body vitamin drinks, the labeling does not reveal the caffeine content. Energy drinks can deliver as much as 360 mg of caffeine (three or four cups of coffee). Symptoms of caffeine intoxication can range from mild nausea and palpitations to severe, protracted vomiting, cardiac dysrhythmias, and seizures.
“Caffeine is really the drug de jour right now, and it is not just in coffee,” Dr. Cooper-DeHoff said.
An energy-enhancement product that was pulled from the shelves several years back, Dr. Cooper-DeHoff added, contained 10,000 times the toxic level of selenium, leading to hair and nail loss in many individuals. Buyers of sexual enhancement products, available on the Internet from all over the world, are not warned that they may contain substances (e.g., sildenafil) that interfere with other conventional medications.
The problem of ingredient inconsistency is exemplified by red yeast rice (Monascus purpureus), a product of yeast grown on rice. Red yeast rice, which is used to lower cholesterol levels, contains monacolin K, the active ingredient in lovastatin (Mevacor, Merck). In various formulations, monacolin K levels can range from less than 1 mg to more than 10 mg per capsule. With a typical recommendation of two capsules twice daily, a person can be taking anywhere from the equivalent of less than 4 mg to more than 40 mg of lovastatin, depending on lot-to-lot fluctuations or manufacturers’ variations. In addition, by-products of the fermentation process include citrinin, a nephrotoxin, and arsenic. Neither the amount of these products nor the amount of monacolin k is listed on the label, because the FDA regulates these products as foods, not as drugs.
“If you have patients who insist on taking this product, it is important that you educate them about what it is and urge them not to vary the amount or switch manufacturers,” Dr. Cooper-DeHoff said.
Co-Q10, often touted as a “miracle” antioxidant, has found many uses (e.g., in hypertension, Alzheimer’s disease, and statin myopathy), but its benefits seem specific to those with a Co-Q10 deficiency. Structurally similar to vitamin K, Co-Q10 can cause a decrease in the INR in patients using warfarin.
Sibutramine (Meridia, Abbott), a weight-loss drug, was pulled from the market in 2010 because of increases in CV events and strokes. However, it is easily available over the Internet.
Bath salts with unlabeled synthetic derivatives that contain amphetamines and cathinones are widespread.
The problem is not the potential interactions and toxicities, Dr. Cooper-DeHoff said; the problem is that patients—77% of them, according to the 2006 AARP survey—are not informing their health care practitioners that they are taking complementary and alternative medications. The reasons given:
The doctor will be dismissive or tell me not to do it (12%).
I don’t think the doctor knows the topic (17%).
There is not enough time during the visit (19%).
I didn’t know I should discuss it (30%).
The doctor never asked (42%).
Thus, case reports of fatal seizures from drug interactions with Ginkgo biloba, rhabdomyolysis caused by natural lipid-lowering agents, and fish-oil interactions with warfarin will continue.
“There is no database collecting information, and we have no idea what the actual adverse event rate is. There is no oversight at the federal level,” Dr. Cooper-DeHoff said.
She concluded, “Always assume your patients are taking at least one supplement and ask! Be highly suspicious in cases where you have done a thorough history but unusual symptoms persist.”
REFERENCE
- 1.Barnes PM, Bloom B, Nahin RL. National Health Statistics Reports. Hyattsville, Md: 2008. Complementary and alternative medicine use among adults and children: United States, 2007. No 12. [PubMed] [Google Scholar]