Recent Advances in Cardiology for the ICU Clinician
Joseph F. Dasta, MSc, FCCM
The Ohio State University
College of Pharmacy
Columbus, Ohio, USA
Jaclyn M. LeBlanc, PharmD, BCPS
The University of Oklahoma
College of Pharmacy-Tulsa
Tulsa, Oklahoma, USA
References
Cardiology is relevant to the intensive care unit (ICU) clinician as patients often are admitted to the ICU with cardiac problems or develop cardiac complications during their stay. Analysis of data from 139 hospitals and more than 180,000 patients with ICU admissions revealed that during 2004 and 2005 the top four diagnoses for ICU patients were coronary atherosclerosis, congestive heart failure, acute myocardial infarction (MI), and nonspecific chest pain and arrhythmias.
These diagnoses accounted for 33% of all patients in the database. The median hospital cost of patients admitted to a coronary care unit (CCU) during this period was $22,800. The cost of CCU patients receiving a transfusion was $49,920 vs $19,920 in the non-transfused cohort. It is clear that cardiac patients consume considerable resources.
Acute Heart Failure
Two conditions, acute heart failure and Acute Coronary Syndrom (ACS), were selected for this review of pharmacologic therapies in cardiac care. Acute heart failure is the most common cause of hospital admissions in patients older than age 65, accounting for 5% to 10% of all hospital admissions. (1) Heart failure registries have been developed to provide insight into current practice patterns.(2)
However, all of these data, including national statistics, apply to patients admitted with acute heart failure. A database review of nearly 500,000 heart failure patients from more than 300 hospitals found that 75% of these patients are discharged with a secondary diagnosis of heart failure. Patients with a secondary diagnosis have higher hospital costs ($20,084 vs $14,350), longer lengths of hospital stay (9.5 days vs 6.4 days), and higher mortality rates (8.1% vs 4.3%) compared to those with a primary diagnosis of heart failure. (3) Perhaps a new classification is in order.
Novel Approaches to Therapy
While therapeutic strategies for acute heart failure have not changed significantly in the past five to 10 years, some novel approaches have been introduced and more are on the horizon. Removal of excess fluid is a mainstay of therapy for symptom relief. Traditionally intravenous (IV) loop diuretics like furosemide are used, but electrolyte distur- bances and diuretic resistance frequently ensue. One of the more novel approaches available is ultrafiltration; new data reveal a significantly greater fluid loss and lower rate of readmission with this method compared to standard therapies. Alternatives to loop diuretics include the recently released dual vasopressin-receptor antagonist conivaptan. This agent is not approved for heart failure, but it mediates an aquaretic effect that could benefit these patients. Adenosine A1 receptor antagonists and opioid-receptor like-1 agonists also are under investigation to promote a water diuresis via different mechanisms. Together, these agents offer the potential to minimize complications of electrolyte disturbances by getting rid of what patients have in excess, namely water.
Although nitroglycerin is used to relieve pulmonary congestion, tolerance and headache limit its use. Instead, healthcare providers are using nesiritide, a synthetic B-type natriuretic peptide that is a vasodilator and diuretic. The flurry of bad press regarding its effects on mortality rates and renal failure has challenged the basic infrastructure of the drug approval and monitoring process in the United States. An expert committee recommended that this drug be used only within labeled indications and that a properly designed clinical trial be conducted. Other natriuretic peptides under investigation include carperitide (human atrial natriuretic peptide) and ularitide (synthetic form of urodilatin), which may have more specific actions. Researchers also are looking into endothelin antagonists for their improved systemic and pulmonary hemodynamic effects. Augmenting cardiac output using parenteral positive inotropes is reserved for severely ill patients, particularly those with cardiogenic shock. Catecholamine inotropes such as dobutamine are used sparingly because they may cause arrhythmias and may accelerate myocyte apoptosis. The results of two large clinical trials involving the investigational calcium sensitizer levosimendan revealed some disturbing
effects on arrhythmia formation and mortality rates.
Preliminary work with myocyte activators looks promising. Despite the magnitude of acute heart failure, current therapies remain inadequate and generally are supportive rather than curative. Patients who are admitted with heart failure or who develop heart failure in the ICU should be managed aggressively.
Acute Coronary Syndrome
More than 1.5 million Americans have ACS as a primary or secondary discharge diagnosis. Heightened interest in the therapy of ACS has led to some “hot” publications. Although the role of anticoagulants and antiplatelets in ACS is well established, identification of the ideal agent remains elusive. Ongoing trials are examining various doses, combinations and timing of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), direct thrombin inhibitors, antiplatelets and the platelet glycoprotein IIb/IIIa (GP) receptor inhibitors. Of late, two trials assessing the role of bivalirudin monotherapy compared to a combination of UFH or LMWH with a GP inhibitor have sparked much interest.
Surprisingly, the PROTECT–TIMI-30 study, which attempted to compare the efficacy and safety of bivalirudin to eptifibatide, found that bivalirudin alone in 857 patients with non-ST segment elevation myocardial infarction (NSTEMI) receiving percutaneous coronary intervention (PCI) had more favorable effects on coronary flow reserve.(4) However, secondary endpoints in this trial were not as favorable with the monotherapy. The ACUITY Trial: Heparins vs. Bivalirudin for ACS, whose findings are still in abstract form, also found positive results with bivalirudin alone. Bivalirudin was superior in the primary composite endpoints, namely death, myocardial infarction (MI), unplanned vascularization for ischemia and major bleeding at 30 days.(5) A recent abstract reported benefits of bivalirudin when REPLACE-2 methodology was used in routine clinical practice for PCI patients who were not at high risk.(6)
A recent meta-analysis of high-dose statins found a 16% reduction in the risk of combined endpoints of coronary death or MI, as well as in coronary death or any cardiovascular event (including MI, stroke, hospitalization for unstable angina, or any revascularization), over standard statin doses.7 The study also showed a nonsignificant trend in reduction of cardiovascular death with the high-dose regimen. The healthcare community is anticipating the publication of the results of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, which may give more insight on the effects of high-dose statins.
On the Horizon
Other agents currently being studied as alternative anticoagulants include apixaban and otamixaban, which are both factor Xa inhibitors. Hexadecasaccharide is a synthetic
heparin mimetic being studied as a treatment in NSTEMI or unstable angina. Researchers are investigating the antiplatelet agents prasugrel and cangrelor as alternatives to clopidogrel. Prasugrel is an irreversible platelet inhibitor in the thienopyridine receptor antagonist class reported to have a higher potency and faster onset of action than clopidogrel. Cangrelor is a short-acting, injectable, reversible anti-platelet agent also being tested in ACS for prevention of thrombotic events.
Several other new therapies are being studied in the ACS setting. Ranolazine, a fatty acid oxidation inhibitor approved by the Food and Drug Administration to treat angina, is being researched as a potential anti-ischemic agent in acute (and chronic) non-ST elevation ACS. Serine proteinase-1, a viral anti-inflammatory serpin, is under investigation as an add-on to conventional therapy in NSTEMI or unstable angina patients requiring early intervention. BXT-51072, a compound that mimics glutathione peroxidase, is being investigated for its potent anti-inflammatory effects and potential cardioprotection in diabetics undergoing elective angioplasty or PCI. The persistence of cardiac disorders and the plethora of therapies on the market and under investigation are good indications that the next few years of cardiovascular research will be very exciting and challenging for the ICU clinician.
