Inexpensive Treatment Could Save Thousands of Heart Attack Victims Black Women Receive Less Cardiac Care Than Whites New Risk Score for Predicting Stroke or Death in Individuals with AF INR Values of 2.0 or Greater Reduce Risk of Death of Ischemic Stroke Inexpensive Treatment Could Save Thousands of Heart Attack Victims Largest Test of Glucose-Insulin-Potassium Infusion Called a Landmark Study A new risk score estimating the risk of stroke or the combination of stroke and death in individuals with atrial fibrillation (AF) has been published in the Journal of the American Medical Association. The risk stratification model examined the predictors of stroke or death in a cohort of community-based individuals with new-onset AF, and researchers conclude that the scores can be used to effectively estimate the risk of an adverse event in these patients. In the subgroup of patients without signs of heart failure at admission, the addition of glucose-insulin-potassium infusion to primary coronary angioplasty significantly reduced mortality. Over nine out of ten patients belong to this subgroup,” said Iwan C. C. van der Horst, MD, at the Hospital de Weezenlanden in Zwolle, Netherlands. It is believed that glucose provides most of the benefit, with potassium and insulin helping the glucose enter heart muscle cells. From April 1998 to September 2001, a total of 940 heart attack patients who were being evaluated for same-day angioplasty treatment were randomly assigned by open-label, to either a continuous glucose-insulin-potassium infusion for 8–12 hours, or to no infusion. All patients went on to receive angiography testing and then angioplasty, if indicated according to usual practice. Overall, there was no statistically significant difference in 30-day death rates for the “no infusion” group (5.8 percent) compared to the patients receiving glucose-insulin-potassium (4.8 percent). However, when 84 patients showing signs of heart failure were removed from the analysis, a clear benefit appeared among the 856 remaining patients. In this subgroup, which included the overwhelming majority of patients, the 30-day mortality was almost 72 percent lower among the patients receiving the infusion (1.2 percent vs. 4.2 percent). Although the researchers said this study does not explain why a glucose-insulin-potassium infusion would not help patients with heart failure, they noted that the large volume of the infusion is a concern. “Also the effect of glucose-insulin-potassium on secondary endpoints is interesting. In this article, the effect of glucose-insulin-potassium on recurrent myocardial infarction and repeat angioplasty are mentioned. The combined endpoint of 30-day mortality, recurrent myocardial infarction and repeat angioplasty was significantly lower in patients without signs of heart failure treated with glucose-insulin-potassium. Even in the overall population, after correction for baseline differences, a strong trend was observed,” Dr. van der Horst said. Despite the dramatic apparent benefit among the majority of heart attack patients in this study, the researchers said their results need to be confirmed. “To change current recommendations on the treatment of patients with acute myocardial infarction, it is likely that a new study has to confirm the beneficial results of the glucose-insulin-potassium infusion,” Dr. van der Horst said. Carl S. Apstein, MD, at the Boston University School of Medicine in Boston, who wrote an accompanying editorial, called the results reported by van der Horst et al. “remarkable”. “I consider this to be a landmark study for the treatment of myocardial infarction,” Dr. Apstein said. “It has the potential to reduce the absolute mortality rate by 3 percent, saving approximately 30,000 lives per year, if one could extrapolate this Dutch study to the U.S., and there’s no reason why one couldn’t.” Dr. Apstein said follow-up studies should be undertaken in the United States, including some that could investigate whether beginning the glucose-insulin-potassium infusion earlier might offer additional benefit. He said that the generic solution is inexpensive and could be easily included in standard therapy if follow-up studies confirm the life-saving benefit seen in this trial. Black Women Receive Less Cardiac Care Than Whites Despite Being at Higher Risk of CHD Mortality Data from the Heart and Estrogen/Progestin Replacement Study (HERS) suggest that black women receive less preventive cardiac therapy and risk-factor control than white women, despite the fact that their risk to develop or to die from coronary heart disease is twice as high. The report, published in Circulation, was the first to compare both cardiac care and clinical outcomes in black versus white women. Racial disparities in cardiac mortality are more pronounced in women than in men, with black women having a more than 30% higher risk of CHD mortality than white women, as reported. Moreover, studies have shown blacks to receive inferior care and risk-factor management in comparison to whites. The present study, headed by Dr. Ashish Jha from Brigham and Women's Hospital in Boston, Massachusetts, is the first to combine the two components, by evaluating racial differences in medical treatment and risk-factor control, as well as CHD outcomes in a large number of women with heart disease, with an average follow-up of 4.1 years. Of the 2,699 study participants, 218 (8.1%) were black. Compared with whites, blacks were younger, less educated, less active, less likely to smoke; had higher BMI and LDL cholesterol levels and lower triglyceride levels; and were more likely to have hypertension, diabetes, congestive heart failure, and renal insufficiency. The researchers found lower rates of aspirin and statin use at baseline among all blacks, as well as those with LDL cholesterol levels higher than > 100 mg/dL, but higher rates of ACE inhibitor use. In addition, cardiac risk factors were controlled less aggressively in blacks than whites, with significantly more black women than white women having systolic blood pressure above 160 mmHg (17% vs. 10%) and LDL cholesterol above 160 mg/dL (38% vs. 30%) at baseline. During follow-up, nonfatal myocardial infarction was twice as common and cardiac mortality was 50% higher in blacks compared with whites, even after adjustment for risk-factor control, medical therapy, and CHD status at enrollment. Other unmeasured factors, the researchers say, must have contributed to the increased event rate in blacks. “Given their increased CHD risk, the lower rates of treatment are concerning,” Jha et al. write. However, they were not able to pinpoint the reasons for these discrepancies. Economic reasons were unlikely, they concluded, because blacks used expensive drugs such as ACE inhibitors and calcium channel blockers. Adherence to drugs and clinical follow-up was similar in black and white women. Physician bias could not be evaluated in their study but might contribute to racial differences in preventive care and drug management, Jha and colleagues suggest. “Though there's no reason to assume malevolent intention on the part of physicians, cultural barriers, stereotypes, and communication barriers all probably play a role in disparities in treatment in general and may have played a role in explaining part of our findings as well,” Jha said. Education and knowledge about cardiac risk factors could also play a role, with women often underestimating their CHD risk. “I firmly believe that education is a key issue and that black women may not adequately perceive their risk of CHD,” said Jha. The next step, he said, would be to design interventions, in particular educational programs targeting black women, that improve risk management and outcomes to narrow the racial gap. Designing such programs would be difficult until disparities are well understood, comment Drs. William Weintraub and Viola Vaccarino from Emory University in Atlanta, Georgia, in an accompanying editorial. They call Jha's paper “provocative,” raising more questions than it answers. Although they concede that blacks are at a greater CHD risk, they are “unsure about the generalizability of this difference.” They point out that in Jha's study, differences in pharmacological therapy were small and that cardiac catheterization and revascularization procedures, for instance, did not differ between blacks and whites. The differences in care, Weintraub and Vaccarino say, had “only a modest effect on outcome.” They suggest genetic differences or environmental influences, perhaps, to account for the differences. In response to Weintraub's criticism, Jha said: “I agree that our paper raises many questions. Foremost, I hope it raises questions about why black women are not treated as aggressively as they clearly should be and what we can do to remedy this.” New Risk Score for Predicting Stroke or Death in Individuals with AF A new risk score estimating the risk of stroke or the combination of stroke and death in individuals with atrial fibrillation (AF) has been published in the Journal of the American Medical Association. The risk stratification model examined the predictors of stroke or death in a cohort of community-based individuals with new-onset AF, and researchers conclude that the scores can be used to effectively estimate the risk of an adverse event in these patients. “There are several trials and pooled analyses examining efficacious therapies to prevent stroke, and warfarin has definitively been proven to significantly reduce these risks,” said senior author Dr. Emelia J. Benjamin from Boston University School of Medicine in Framingham, Massachusetts. “However, many of the patients that we wish to anticoagulate are elderly or have other comorbidities and are at an increased risk of bleeding with warfarin. That’s why we really need to understand the risks of having a bad outcome, so that we can effectively weigh the benefits and risks of a therapy that is not necessarily benign.” To derive risk scores for stroke alone and stroke or death in individuals with new-onset AF, Benjamin and colleagues identified 868 patients, of whom 705 were not treated with warfarin at baseline. Investigators conducting the prospective, observational cohort analysis included participants in the original and offspring cohorts of the Framingham Heart Study aged 55 to 94 years at the time of AF diagnosis. Participants with an adverse event reported within the first 30 days following AF were excluded from the study. “Most of the prior studies that have looked at the risk factors for stroke in atrial fibrillation have been based on randomized, controlled trials,” Benjamin said. “However, many of the patients in these studies are younger, more likely to be men, and have fewer comorbidities than patients in the community with atrial fibrillation. We felt it would be a good idea and the right time to look at the risk factors in a community-based setting.” The risk score for stroke was derived from five risk predictors: advancing age, female sex, increasing systolic blood pressure, prior stroke or transient ischemic attack (TIA), and diabetes. The risk score for combination of stroke and death included the following risk predictors: advancing age, increasing systolic blood pressure, smoking, prior MI or CHF, diabetes, heart murmur, and LVH as determined by ECG. For an individual patient, the probability of stroke was estimated by calculating a point score based on the risk-factor information. Analyses were performed before and after the exclusion of subjects taking warfarin, and the warfarin-censored analyses were used as the primary models in the development of the risk scores and calculation of the events rate. During a mean follow-up of 4 years free of warfarin use, stroke alone occurred in 83 participants and the combination of stroke or death occurred in 382 patients. On the basis of the derived risk score, 14.3% of the cohort had a predicted five-year stroke rate of < 7.5%, and 30.6% of the cohort had a predicted five-year stroke rate of < 10%. Actual stroke rates in these low-risk groups were 1.1 and 1.5 per 100 person-years, respectively. Previous risk prediction models classified 6.4% to 17.3% of subjects as low risk, note investigators. “We can identify people at a particularly low risk or particularly high risk to stratify these patients, potentially plan for therapy, and give people a sense of what their prognosis is,” said Benjamin. “Part of this is by being able to establish the level of risk that you are willing to accept when treating these patients.” Benjamin points out that echocardiographic findings were not included in the risk scores. As a result, the risk scores may underestimate the risk of stroke for individuals with significant LV systolic dysfunction. Individuals treated with warfarin were also excluded from the models used to derive the risk scores, note the investigators, possibly removing some of the highest-risk individuals from the analysis. Benjamin adds the Framingham cohort was predominantly white, potentially affecting the risk stratification model. “One of the important caveats is that the risk score needs to be validated in other databases,” said Benjamin. “We don't necessarily know if this instrument is going to apply to other ethnicities.” In an editorial accompanying the published study, Dr. Albert L. Waldo from Case Western Reserve University in Cleveland, Ohio, writes that determining which patients with AF should receive oral anticoagulation therapy is a critical question. For each patient, clinicians must strike an acceptable balance between their patients' risk of ischemic stroke and risk of bleeding, he adds. “In the absence of an absolute or important relative contraindication, the data seem compelling that warfarin therapy should be offered to patients with AF at risk of stroke,” writes Waldo. “The difficulty is to know what threshold of stroke risk is low enough so that the potential risks of warfarin therapy outweigh its potential benefits.” Waldo writes that patients with AF, especially elderly patientswho would be good candidates for warfarin therapy, often do not receive treatment. The most noteworthy concern limiting the use of warfarin therapy is the risk of bleeding, especially from falls, frailty, or forgetfulness, he adds. “For most patients, the potential benefits of stroke prevention will outweigh the potential risks of bleeding secondary to warfarin,” concludes Waldo. “Considering that accurate risk stratification is essential to identify patients who have the best chance of benefit from anticoagulant therapy, clinicians should find the Framingham risk scoring system a useful aid for clinical decision-making.” INR Values of 2.0 or Greater Reduce the Frequency, Severity, and Risk of Death of Ischemic Stroke in Patients with Nonvalvular AF Among patients with nonvalvular atrial fibrillation, the results of a recently published study indicate that the intensity of anticoagulation therapy reduces not only the frequency of ischemic stroke but also its severity and risk of death from stroke. The results, conclude investigators, support the use of anticoagulation to achieve an international normalized ratio (INR) of 2.0 or greater. The results are published in a recent issue of the New England Journal of Medicine. “Any anticoagulant therapy has the risk of hemorrhage associated with it,” Lead investigator Dr. Elaine Hylek from Massachusetts General Hospital in Boston, Massachusetts, said. “What this study is showing is that if you are really concerned about the risk of bleeding, you have to be aware that if you target INR levels less than 2.0, we now know you are potentially exposing the patient to the risk of having a more severe stroke and of having higher mortality post-stroke.” Nonvalvular atrial fibrillation (AF) increases the risk of ischemic stroke by as much as a factor of five. While warfarin is highly effective in preventing stroke in patients with AF — most likely by minimizing the formation of atrial thrombi — the full effect of anticoagulation is seen at an INR of 2.0 and above, said Hylek. To assess the effect of intensity of anticoagulation on the severity of ischemic stroke and on the 30-day mortality rate poststroke, investigators examined a large cohort of 13,550 patients with nonvalvular AF. All patients enrolled in the study were 18 years or older and presented with nonvalvular AF between July 1996 and December 1997. During the study period, 596 patients with AF and ischemic stroke were identified. Of these patients, 188 (32%) were taking warfarin at the time of their stroke, 160 (27%) were taking aspirin, and 248 (42%) were taking neither warfarin nor aspirin. The severity of stroke was categorized according to the extent of the neurologic deficit at discharge: severe (or in-hospital death), major, minor, or no deficit. Of the patients with a severe stroke, 39% died within 30 days after discharge compared with 13% of those with a major deficit and 1% with a minor deficit. “The reason we looked at the severity of stroke at the time of discharge and then looked mortality is that you want to have some confidence that it is the stroke itself that is leading to increased mortality,” said Hylek. “What we saw was a very tight correlation between mortality and stroke severity.” Among the 188 patients taking warfarin, 15% of those with an INR < 2.0 on admission to the hospital experienced a severe stroke or died in the hospital, compared with only 5% of patients taking warfarin who had an INR >= 2.0. Among patients taking warfarin at the time of stroke who had an INR >= 2.0, 6% died within 30 days, compared with 16% of stroke patients with an INR < 2.0. The 30-day mortality rate of patients taking aspirin at the time of stroke was nearly identical (15%) to the rate among patients taking warfarin who had an INR < 2.0. The 30-day mortality rate among patients who were taking neither warfarin nor aspirin was 24%. Notably, there was no marked increase in the absolute rate of intracranial hemorrhage at INR values of less than 4.0. Hylek said the large cohort and the large number of patient-years should give physicians confidence in prescribing anticoagulation to target INR levels of 2.0 or greater. “It is often difficult to strike that balance between the bleeding risk and risk of losing the efficacy of drug. Physicians — hoping to do no harm — are always trying to figure out what intensity of anticoagulation would be the safest,” said Hylek. “However, the risks of hemorrhage do not take off appreciably until we reach INR levels of 4.0.” In a perspective accompanying the published study, Dr. Robert G. Hart from the University of Texas Health Science Center in San Antonio writes that antithrombotic therapies are best tailored according to the risk of stroke and bleeding during anticoagulation. Hart writes that while warfarin is “unequivocally superior” to aspirin therapy for the prevention of stroke in patients with AF, not all patients with AF should receive lifelong anticoagulation. “Adjusted-dose warfarin offers large benefits for high-risk patients with atrial fibrillation, whereas aspirin is adequate for low-risk patients,” writes Hart. “For those at moderate risk, the patient's preference, the individual risk of bleeding during anticoagulation, and access to high-quality anticoagulation monitoring are crucial factors in the decision to use warfarin rather than aspirin.” Hart writes that agents more efficacious aspirin and easier to use than adjusted-dose warfarin are needed. He notes several large, randomized trials are testing novel oral anticoagulants and combinations of antiplatelet agents as options for stroke prevention.
