Statins for Stroke Prevention
By Paul J. Grant, MD
Amarenco P, Bogousslavsky J, Callahan A III, et al. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006 Aug 22;355:549-559.
Despite recent advances, the physician’s armamentarium for secondary stroke prevention is limited. The literature regarding optimal blood pressure management for stroke prevention is sparse, and the data addressing the best antiplatelet regimen remain controversial. This is troubling, given the fact that cerebrovascular disease remains the third leading cause of death in the United States.
Although extensive data exists for the benefits of using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) for the prevention and treatment of cardiovascular disease, little is known about their role in decreasing the risk of stroke. The highly anticipated Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial sought to determine if statin therapy would decrease the risk of recurrent stroke in patients with no known coronary heart disease.
This prospective, randomized, double-blind, placebo-controlled trial included 4,731 men and women with no history of coronary heart disease. Eligible patients had a history of stroke (ischemic or hemorrhagic) or a transient ischemic attack (TIA) within a one- to six-month period before randomization as diagnosed by a neurologist. All patients required a low-density lipoprotein (LDL) cholesterol level between 100 and 190 mg/dL, while exclusion criteria included atrial fibrillation. Patients were randomized either to a dosage of 80 mg of atorvastatin daily or to a placebo and were followed for a median duration of 4.9 years. The primary endpoint was fatal or nonfatal stroke.
The average patient age in this trial was 63; approximately 60% of the patients were male. A total of 265 patients reached the primary endpoint in the atorvastatin group, versus 311 patients in the placebo group. This translates to an adjusted relative risk reduction of 16% in the primary endpoint for patients receiving atorvastatin (hazard ratio 0.84; 95% confidence interval 0.71 to 0.99; p=0.03). Although there was no difference in overall mortality between the two groups, the incidence of cardiovascular events was significantly lower in those receiving atorvastatin. Interestingly, more hemorrhagic strokes were noted in the atorvastatin group. With respect to safety, no significant differences in serious adverse events were noted. The atorvastatin group did, however, encounter significantly more cases of persistently elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT), at 2.2% versus 0.5% in the placebo group.
The findings by the SPARCL investigators provide strong evidence that atorvastatin reduces the incidence of stroke recurrence. The mechanism for risk reduction with statin exposure is most likely due to the dramatic lowering of LDL cholesterol. This effect has been shown in numerous trials resulting in the reduction of cardiovascular events. The present trial observed a 53% decrease in LDL cholesterol in the atorvastatin group compared with no change in the placebo arm. In addition to their powerful lipid-lowering role, statins also appear to prevent plaque rupture, optimize endothelial function, and provide anti-inflammatory effects. These are the so-called “pleiotropic effects” of statins and may be another factor contributing to the benefits observed.
Although some physicians are already prescribing statins for stroke patients, the literature supporting this practice has been sparse. The latest guidelines for prevention of stroke in patients with ischemic stroke or TIA were published in February 2006 by the American Heart Association/American Stroke Association Council on Stroke. These guidelines state that patients with a history of ischemic stroke or TIA are “reasonable candidates” for statin therapy. One could argue that these guidelines should now be revised to include a strong recommendation for statin therapy in secondary stroke prevention.
MRSA in the Community
By Matthew T. Harbison, MD
Moran GJ, Krishnadasan A, Gorwitz RJ, et al. EMERGEncy ID Net Study Group. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med. 2006 Aug 17;355(7):666-674.
Methicillin-resistant Staphylococcus aureus (MRSA) emerged as an issue in the healthcare community not long after the introduction of methicillin in 1959. MRSA has traditionally been thought of as an issue for those individuals who have contact with the healthcare system; however, there is growing evidence that MRSA has become an entity in the greater community at large, affecting individuals who have not spent significant time in healthcare facilities. Descriptions of several community-based outbreaks have led to the understanding that community-associated MRSA has different characteristics than MRSA infections contracted in the hospital setting. The community-associated isolates are resistant to fewer antibiotics, produce different toxins, and have differing genetic complexes responsible for antibiotic resistance. The majority of the community-acquired infections are skin and soft tissue infections, although more serious infections have been reported.
Moran and colleagues conducted a prospective prevalence study in adult patients presenting to emergency departments with skin and soft tissue infections in 11 metropolitan areas in geographically diverse regions of the United States. Eligible patients 18 and older with purulent skin or soft tissue infections of less than one week’s duration had demographic and historical data collected; a wound culture was also taken. If Staphylococcus aureus was isolated, it was further evaluated by the Centers for Disease Control and Prevention (CDC) to characterize antibiotic resistance patterns, toxin production, and the type of staphylococcal cassette chromosome present.
A total of 422 patients were enrolled, with S. aureus isolated in 320 patients (76%). Of those with isolated S. aureus, 78% had MRSA (59% of the total patients enrolled). The individual site prevalence of MRSA ranged from 15 to 74% and was the predominant etiology of skin and soft tissue infections in 10 of 11 emergency departments. MRSA susceptibilities in this study were 100% to trimethoprim-sulfamethoxazole and rifampin, 95% to clindamycin, 92% to tetracycline, 60% to fluoroquinolones, and 6% to erythromycin. The authors point out that clindamycin resistance in one center was 60%; thus, individual site resistance patterns may differ significantly. Treatment data was available for 406 of the 422 patients, with the majority of those treated with incision, drainage, and antibiotics. In 100 of the 175 MRSA patients treated with antibiotics, the choice of agent was discordant with susceptibility patterns. The authors were able to contact 248 patients between two and three weeks after their visits and, of those contacted, 96% reported resolution or improvement of the wound.
Using multivariate logistic-regression analyses, the authors identified several potential risk factors for MRSA infection. These included use of any antibiotic in the past month, underlying illness, history of MRSA infection, close contact with someone with similar infection, and reported spider bite. Interestingly, being a healthcare worker, living in a long-term care facility, and being hospitalized in the past year were not shown to be significant risk factors in this study.
The results of this study highlight the emerging difficulty, which continues to evolve, with antibiotic resistance patterns. The healthcare community must be vigilant to new entities that challenge the traditional views of antibiotic resistance patterns. The high rate of community-acquired MRSA skin and soft tissue infection demonstrated in this study, in addition to the large percentage of patients prescribed antibiotics that were resistant for the strain involved, emphasizes the need to reconsider the empiric antibiotic choices for this patient population. The variability in regional resistance patterns further complicates the issue. Given the high prevalence of MRSA skin and soft tissue infections reported in this study, use of routine wound cultures appears prudent, as does the need for effective follow-up strategies for alteration of antibiotic choice if necessary. At an institutional level, development of surveillance and isolation strategies for community-acquired MRSA should be considered.
More Options for Venous Thromboembolism Treatment
By Kirsten N. Kangelaris, MD
Kearon C, Ginsberg JS, Julian JA, et al. Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug 23;296(8):935-942.
The standard approach to using unfractionated heparin (UFH) in the treatment of acute venous thromboembolism as a bridge to warfarin therapy requires continuous intravenous infusion with frequent dose adjustments in response to measurements of activated partial thromboplastin time (aPTT). This therapy inevitably requires inpatient management. Subcutaneous administration of weight-based low molecular weight heparin (LMWH) has been the modality of choice for outpatient treatment of venous thromboembolism because it does not require laboratory monitoring. Its use has been limited by the high cost of treatment, however. A preliminary study, released in 2000 by the FIDO group (Fixed-Dose Heparin Investigators, Kearon and colleagues), suggested that subcutaneously administered UFH could be optimally dosed based on weight rather than monitoring aPTT levels.
This follow-up, randomized, open-label, adjudicator-blinded, multi-centered, non-inferiority trial enrolled 708 patients and compared fixed-dose, subcutaneously administered UFH to LMWH in acute deep venous thrombosis and pulmonary embolism. Administration in both groups was twice daily, subcutaneous, and weight-based. UFH was given as a first dose of 333 U/kg, followed by 250 U/kg every 12 hours. LMWH was administered at a dose of 100 IU/kg every 12 hours. Both treatments overlapped with three months of warfarin therapy, and both could be administered out of hospital.
Exclusion criteria were age <18, contraindication to subcutaneous therapy, active bleeding, life expectancy under three months, long-term anticoagulation therapy, pregnancy, and creatinine level >2.3 mg/dL.
The primary endpoints were efficacy as determined by recurrent venous thromboembolism within three months and safety as determined by major bleeding within 10 days of randomization. A secondary endpoint was relationship of efficacy and safety outcomes to aPTT levels measured on day two to three of therapy for the UFH group.
Results revealed that UFH was statistically non-inferior to LMWH by all endpoints, including treatment duration, efficacy, and safety. At three months, there was no significant difference between the groups in frequency of recurrent venous thromboembolism (3.8% UFH versus 3.4% LMWH), bleeding (1.1% UFH versus 1.4% LMWH), or death. There was no association between aPTT levels and recurrent venous thromboembolism or bleeding.
Limitations of the study included reduced enrollment from the initial study design, though power was adequate due to a lower than expected incidence of recurrent venous thromboembolism in both arms (~3.6% versus the expected 6%); possible biases related to open-label design; and more post-randomization exclusions in the UFH group versus the LMWH group.
In summary, fixed-dose, unmonitored, subcutaneous UFH appears to be an effective, safe alternative to LMWH as a bridge to warfarin therapy for venous thromboembolism. Clinically, this is relevant, because UFH is approximately 15 to 20 times less expensive than LMWH. The authors appropriately call attention to two developments in clinical practice that occurred during the course of the present study and that could potentially limit the use of UFH. These are 1) the dosing option for once-daily LMWH, which improves convenience, and 2) the preference for long-term LMWH therapy over warfarin for treating cancer patients with venous thromboembolism. Despite these exceptions, UFH may prove to be a viable and economic option for venous thromboembolism treatment.
In-Hospital MI Versus MI at Presentation
By Erin M. Galbraith, MD
Maynard C, Lowy E, Rumsfeld J, et al. The prevalence and outcomes of in-hospital acute myocardial infarction in the Department of Veterans Affairs Health System. Arch Intern Med. 2006 Jul 10;166(13):1410-1416.
Much is known about the prevalence, treatment, and prognosis of acute myocardial infarction (AMI) when it occurs in the community and is the presenting diagnosis. Few studies, however, have addressed the epidemiology of in-hospital AMIs. This study by Maynard and colleagues attempts to elucidate the basic epidemiologic characteristics, treatments, and outcomes of patients who suffer in-hospital AMIs.
This retrospective cohort consisted of 7,054 patients who had been discharged with a diagnosis of AMI from 127 Veterans Health Administration (VHA) medical centers between July and August 2003. Patients who had suffered a postoperative MI or were transferred in from another hospital were excluded. Data was obtained from both the electronic and paper medical records. Of the 7,054 patients in the study, 792 (11.2%) had experienced an AMI while hospitalized for other medical problems. These 792 patients were older by approximately 4.5 years and more frequently suffered from heart failure, diabetes, chronic renal insufficiency, COPD, cerebrovascular disease, dementia, and cancer. These patients were less likely, however, to have had a previous MI, to be current smokers, or to have undergone previous angioplasty. They were also less likely to have known lipid disorders or to be taking aspirin or lipid-lowering agents.
Regarding their presentations and management, the patients who suffered in-hospital AMIs had faster heart rates and lower blood pressures. They were also up to 75% less likely to report typical symptoms of cardiac ischemia, including chest pain/pressure, shoulder pain, nausea, and diaphoresis. They were less often seen by an attending cardiologist and had more contraindications to AMI therapy; thus, these patients underwent reperfusion therapy at much lower rates, both initially and at 30 days. Their troponin levels were more frequently elevated, but they were only half as likely to have ST segment elevations at the time of diagnosis. Hospitalizations were longer for the in-hospital group, and there were higher rates of in-hospital cardiogenic shock, cardiac arrest, and death (27.3% versus 8.6%). The 30-day mortality rate was also higher (33% versus 11.9%). Multivariate logistic regression revealed an adjusted odds ratio of 2.0 (95% confidence interval 1.7 to 2.4; p<0.001) for 30-day mortality in those who experienced an in-hospital AMI versus those who presented with an AMI.
Potential reasons for the increased severity of outcomes include, but are not limited to, their many chronic comorbidities, their other acute diagnoses, the failure of the medical team to recognize cardiac ischemia in a timely manner (i.e., higher initial troponins), the inability to treat MIs appropriately secondary to contraindications to acute intervention, and the lack of an attending cardiologist presiding over their medical care. Clearly, further studies are needed to elucidate the causes of death in the 33% of patients who died, because it is unclear whether the patients died of complications from their MIs or as a result of their multiple other medical problems. Knowledge of the extent to which these patients could be managed, both medically and via interventional procedures (and why these therapies were not pursued), would also be of value.
This study emphasizes the importance of recognizing atypical presentations of AMIs and exercising vigilance in pursuing the most aggressive therapy possible, as dictated by a patient’s ability to tolerate medical and procedural interventions.
Hyperglycemia in Heart Failure
By David H. Wesorick, MD
Barsheshet A, Garty M, Grossman E, et al. Admission blood glucose level and mortality among hospitalized nondiabetic patients with heart failure. Arch Intern Med. 2006 Aug 14-28;166(15):1613-1619.
The medical literature strongly suggests that inpatient hyperglycemia is associated with a variety of poor outcomes. Little is known, however, about the relationship between hyperglycemia and heart failure. These investigators examined the association of admission blood glucose and mortality in patients who were admitted to the hospital with acute heart failure.
In this study, 1,122 patients admitted to the hospital with acute heart failure and without diabetes were divided into tertiles depending on their admission blood glucose levels. Diabetes was defined as an admission blood glucose greater than or equal to 200 mg/dl, a known diagnosis of diabetes recorded in the chart, or the presence of anti-diabetic medications on the patient’s medication list. Tertile #1 had an average admission blood glucose of 92 mg/dl (with a range of 54-102); tertile #2 had an average admission blood glucose of 113 mg/dl (with a range of 103-127); and tertile #3 had an average admission blood glucose of 147 mg/dl (with a range of 128-199). Mortality was evaluated according to tertile.
In this study, patients in tertile #3 had significantly higher inpatient mortality (7.2%) than patients in tertile #1 or #2 (3% and 4%, respectively). There was a significant association between hyperglycemia and mortality, even at 60 days follow-up, although not at six and 12 months follow-up. The association remained significant, even when patients with acute MI were excluded. Besides hyperglycemia, the authors noted that increasing age, increasing creatinine, a New York Heart Association (NYHA) functional class of III or IV, and a systolic blood pressure of lower than 115 were also significant, independent predictors of in-hospital mortality in this patient population.
For a hospitalist, the intriguing question is this: Is hyperglycemia just a marker of worse disease, or might it contribute to poorer outcomes? Clearly, hyperglycemia is associated with poorer outcomes in other types of patients, including post-surgical patients, critically ill patients, MI patients, and general medical patients.1 But is hyperglycemia just a marker of more severe illness? In heart failure, perhaps more severe decompensation results in a more profound activation of the sympathetic nervous system and a more vigorous release of stress hormones, such as cortisol and catecholamines. In that case, one might expect a sicker patient to have a higher blood glucose.
More recent studies, however, show that better control of hyperglycemia in some acutely ill patients actually results in improved outcomes, suggesting that the hyperglycemia itself might be contributing to the poorer outcomes in some cases.2-5 Hyperglycemia is known to alter human physiology in a variety of adverse ways.1 For example, hyperglycemia is known to inhibit nitric oxide production and to alter endothelial dysfunction. In a patient with acute heart failure, these alterations might be expected to have a significant effect on outcomes.
This study does not intend to answer these questions, but it does add to our understanding of the association of hyperglycemia and poor outcomes in acutely ill patients. More research is needed to examine whether or not heart failure patients, specifically, will benefit from better glycemic control in the acute setting. TH
- Clement S, Braithwaite SS, Magee MF, et al. Management of diabetes and hyperglycemia in hospitals. Diabetes Care. 2004 Feb;27(2):553-591.
- Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001 Nov 8;345(19):1359-1367.
- Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006 Feb 2;354(5):449-461.
- Furnary AP, Zerr KJ, Grunkemeier GL, et al. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg. 1999 Feb;67(2):352-362.
- Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2003 May;125(5):1007-1021.