James J. Nawarskas

Effect of aspirin on blood pressure in hypertensive patients taking enalapril or losartan

The ability of angiotensin converting enzyme (ACE) inhibitors to lower blood pressure may in part be due to the formation of vasodilatory prostaglandins. Inhibition of prostaglandin synthesis with aspirin may therefore theoretically attenuate the antihypertensive effect of ACE inhibitors. This trial studied the interaction between aspirin (ASA) and enalapril, an ACE inhibitor, and ASA and losartan, an angiotensin subtype 1 receptor antagonist. Seventeen essential hypertensive patients were studied, maintained on a stable dose of either enalapril (n = 7) or losartan (n = 10) monotherapy for > or =12 weeks before and throughout the study. Each patient received a 2-week course of placebo, 81 mg/day ASA, and 325 mg/day ASA, each treatment separated by a 2-week washout period. Blood pressure (BP) and serum thromboxane B2 (TXB2) samples were obtained at the end of each treatment period. Placebo was compared with each dose of ASA for each group. In both the enalapril and losartan groups, mean, systolic, and diastolic BP were unchanged with the addition of ASA. Concentrations of TXB2 were suppressed to <10% in both groups with ASA. This study demonstrates that 81 to 325 mg/day ASA exerts no significant effect on BP in essential hypertensives taking enalapril or losartan.

Pharmacotherapeutic management of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a disabling chronic disorder of the pulmonary vasculature, which is characterized by increased pulmonary artery pressure as a result of increased pulmonary vascular resistance. The pathology of PAH is characterized by pulmonary vascular vasoconstriction, smooth muscle cell proliferation, and thrombosis. These changes are a result of an imbalance between vasodilators (prostacyclin, nitric oxide, vasoactive intestinal peptide) and vasoconstrictors (thromboxane A2, endothelin, serotonin), growth inhibitors and mitogenic factors, and antithrombotic and prothrombotic factors. Recent advances in treatment are directed at restoring the balance between these systems. Endothelin receptor antagonists (bosentan, ambrisentan, sitaxsentan), phosphodiesterase type 5 inhibitors (sildenafil, tadalafil), and prostacylin (epoprostenol, iloprost, treprostinil, beraprost) represent the different classes of medications that are currently used in monotherapy and in combination to treat PAH. The purpose of this drug highlight is to provide the reader with an update of the pharmacotherapeutic treatment of PAH.

Ticagrelor: a novel reversible oral antiplatelet agent.

The complex mechanism of platelet activation creates an optimal target for pharmacological treatment in patients with acute coronary syndromes. Current antiplatelet medications that are used in addition to aspirin include the thienopyridines, clopidogrel and prasugrel, but there are several limitations to the use of these medications. Clopidogrel and prasugrel irreversibly bind to the P2Y12 receptor, creating a prolonged antiplatelet effect which can be undesirable when surgery is needed. Clopidogrel requires hepatic activation and produces variable platelet inhibition based on genetic polymorphisms. Prasugrel has more consistent platelet inhibition than clopidogrel but carries with it an increased risk of serious bleeds. Ticagrelor is a drug in a new chemical class that reversibly binds the P2Y12 receptor and noncompetitively blocks adenosine diphosphate-induced platelet activation. It was specifically designed to address the limitations of the available antiplatelet agents while maintaining comparable or better antiplatelet effects. It does not require metabolic activation and demonstrates greater platelet inhibition, a faster offset of action and comparable bleeding risk compared to clopidogrel. The pivotal PLATO (The Study of Platelet Inhibition and Patient Outcomes) trial in patients with an acute coronary syndrome demonstrated improved cardiovascular outcomes, including a reduction in myocardial infarctions and vascular events using ticagrelor as compared to clopidogrel with comparable rates of major bleeds. A puzzling finding from that trial was the lack of benefit with ticagrelor in patients enrolled from the United States, which has led to ticagrelor not being approved at this time in this country. The main adverse events with ticagrelor are bleeding and dyspnea, the latter of which is of unclear etiology and of unknown long-term clinical concern. In summary, ticagrelor is an exciting new oral antiplatelet drug that seems to be more efficacious than clopidogrel, with comparable safety. Whether issues of geographic disparities in response and the unusual side effect of dyspnea ultimately prove problematic has yet to be determined. Nonetheless, ticagrelor is a drug that has the potential to change the standard of care of patients with acute coronary syndromes.

Does Aspirin Interfere with the Therapeutic Efficacy of Angiotensin-converting Enzyme Inhibitors in Hypertension or Congestive Heart Failure?

We conducted a MEDLINE search of published literature from 1966 to January 1998 regarding the impact of aspirin (ASA) on the therapeutic effect of angiotensin‐converting enzyme (ACE) inhibitors in hypertension and congestive heart failure. Selected references from these articles and results of recent clinical trials were also included. By inhibiting cyclooxygenase, ASA may interfere with the prostaglandin‐mediated hemodynamic effects of ACE inhibitors. Although other nonsteroidal antiinflammatory drugs may increase blood pressure in hypertensive patients taking an ACE inhibitor, low‐dosage (≤ 100 mg/day) ASA does not. However, higher dosages of ASA may attenuate the benefits of ACE inhibitors in patients with hypertension and/or congestive heart failure (CHF). Low‐dosage ASA appears to interact little with ACE inhibitors, whereas higher dosages may produce a more significant interaction. Patients with CHF may also be more susceptible to this interaction because of underlying disease.

Digoxin Toxicity Secondary to Clarithromycin Therapy

OBJECTIVE: To report a case of digoxin toxicity thought to be secondary to clarithromycin therapy. CASE SUMMARY: A 78-year-old white woman with congestive heart failure taking digoxin 0.25 mg po qd presented to our hospital with nausea, vomiting, and diarrhea. She had taken clarithromycin 500 mg po bid for 3 days, and a serum digoxin concentration obtained the day of admission was 4.4 μg/L. An electrocardiogram (ECG) done on admission revealed ST segment changes consistent with digoxin effect and later asymptomatic, nonsustained ventricular tachycardia (NSVT). Clarithromycin was discontinued and digoxin was withheld at admission, resulting in the resolution of symptoms, ECG abnormalities, and NSVT on day 3 of hospitalization. On day 5 her serum digoxin concentration was 1.5 μg/L and digoxin therapy was reinstituted at a dose of 0.125 mg/d po. DISCUSSION: This is the fourth published case implicating clarithromycin as the cause of digoxin toxicity. This interaction is most likely due to clarithromycin eradication of digoxinmetabolizing gut flora, thereby increasing digoxin bioavailability. CONCLUSIONS: Approximately 10% of patients are thought to be extensive presystemic metabolizers of digoxin and may therefore be most susceptible to a drug interaction with clarithromycin. Serum digoxin concentrations in such patients should be monitored closely during clarithromycin therapy.

Misadventures with Activated Charcoal and Recommendations for Safe Use

OBJECTIVE: To review published reports of adverse effects associated with single- and multiple-dose activated charcoal therapy, and to formulate recommendations for safe use of activated charcoal therapy. DATA SOURCES: A manual search of Index Medicus from 1970 to December 1993 was conducted for English language articles; bibliographies of the resultant articles were also scanned. STUDY SELECTION: Cases were included if they were described in full detail, resulted in significant morbidity or mortality, and uniquely contributed to the formulation of recommendations for safe use of activated charcoal therapy. DATA SYNTHESIS: The major causes of morbidity and mortality secondary to activated charcoal therapy are aspiration of charcoal, gastrointestinal obstruction, and fluid and electrolyte abnormalities. Aspirations have occurred as a result of a number of circumstances that may be avoided. These include use in patients with unprotected airways, use of excessive charcoal dose, administration of inappropriately diluted charcoal, and administration of charcoal in the field. Gastrointestinal obstruction has occurred when multiple doses of activated charcoal have been administered without a cathartic and in cases in which a cathartic was administered if the patient had impaired peristalsis. Fluid and electrolyte abnormalities have occurred secondary to excessive cathartic administration. CONCLUSIONS: Activated charcoal therapy should be used judiciously so that related morbidity and mortality can be prevented. Adequate consideration for the patients airway protection capability is necessary. Judicious dosing of charcoal and concomitant cathartic therapy, along with adequate monitoring of fluid and electrolyte status, abdominal physical assessment, and clinical condition are all vital to the safe use of activated charcoal therapy.

Variability of response to clopidogrel: possible mechanisms and clinical implications.

Clopidogrel has been shown to inhibit adenosine diphosphate-induced platelet aggregation and has been demonstrated to be effective in reducing the risk of arterial thrombotic events in several large clinical studies. However, the clinical benefit could be attenuated by the variability of response to the antiplatelet effects of clopidogrel in as many as 30% of patients. Multiple mechanisms likely contribute to clopidogrel variability of response, including inappropriate dosing or underdosing of clopidogrel, drug–drug interactions, and genetic polymorphisms. The best laboratory procedure to screen for possible clopidogrel variability of response remains to be determined.

Clinical Presentation and Analysis of Risk Factors for Infectious Complications of Implantable Cardioverter-Defibrillator Implantations at a University Medical Center

The objective of this report is to describe the characteristics of patients who develop infections associated with implantable cardioverter-defibrillators (ICDs) implanted with sternotomy and thoracotomy approaches. A retrospective chart review identified all patients who underwent ICD implantation at a university medical center from November 1982 through February 1990. Several patient and procedural variables were compared between infected patients and noninfected patients. One hundred fifty-seven patients underwent 202 ICD generator implantations (45 generator changes), and nine of these patients developed infection (4.5% per implantation and 5.7% per patient). Of the patient variables analyzed, a significant correlation (P < .0001) was made only with a diagnosis of diabetes mellitus: 36% of diabetics versus 3.9% of nondiabetics were infected. The only patient- or procedure-specific variable that was found to correlate with the development of infection was the presence of diabetes mellitus.

Hydrochlorothiazide versus chlorthalidone in the management of hypertension.

Thiazide diuretics are a mainstay for the treatment of hypertension. Although there are several thiazide diuretics currently available, hydrochlorothiazide (HCTZ) continues to be the most popular thiazide used for treating high blood pressure. This is despite several clinical trials that have used and documented the benefits of chlorthalidone for hypertension management. In terms of blood pressure lowering, both HCTZ and chlorthalidone appear to be very effective. Head-to-head studies have shown trends favoring chlorthalidone as a more effective blood pressure lowering agent compared with HCTZ, but statistical significance in this regard has not been consistently demonstrated. Also unclear is the relative benefits of these 2 drugs with regards to reducing clinical complications of hypertension, namely cardiovascular morbidity and mortality. Whereas there is more aggregate clinical trial data documenting the benefits of chlorthalidone compared with HCTZ in terms of hard clinical outcomes, these trials are not direct comparisons and can only be used to fuel the debate as to which of the 2 thiazides are better. From a safety perspective, hypokalemia is a risk with any of the thiazide diuretics and has been shown to be dose-related. However, at equipotent dosages, the incidence of hypokalemia between chlorthalidone and HCTZ appears comparable. The available evidence therefore supports both HCTZ and chlorthalidone as safe and effective drugs for treating hypertension. Although there are favorable trends both in terms of antihypertensive efficacy as well as clinical outcomes data with chlorthalidone compared with HCTZ, the results are not conclusive, and as such may not be enough to shift the treatment paradigm in favor of chlorthalidone, given the comfort level that most prescribers have with HCTZ. A head-to-head study looking at hard clinical outcomes, which may or may not ever be performed, may be the only way to resolve the ongoing debate as to which is the preferred thiazide for treating hypertension.

Prasugrel: a new antiplatelet drug for the prevention and treatment of cardiovascular disease.

Prasugrel, trade name Effient, is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration. It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine. Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic P2Y12 receptor on the platelet surface. Prasugrel has been shown to be a potent antiplatelet agent with a faster, more consistent, and greater inhibition of platelet aggregation compared with clopidogrel. It is debatable, however, how effectively these pharmacologic benefits will translate to clinical benefits. The results of the large TRITON-TIMI 38 trial, which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents, demonstrated a significant reduction in ischemic events, including stent thrombosis, with prasugrel, but with an increased risk of major bleeding. The exact role of prasugrel in the management of ischemic heart disease is still being defined, but the risk:benefit ratio will likely play a major role in directing the best place for therapy with this new agent.