American College of Cardiology: Encapsulated Pravastatin for HIV Infection in Patients with Dyslipidemia

HIV InfectionSpeaker: Matthew K. Ito, PharmD, Professor and Vice Chair, Pharmacy Practice Department, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, California.

Dyslipidemia is a common side effect of protease inhibitor therapy in HIV-infected patients. An encapsulated form of pravastatin appears to offer a new efficacious therapeutic approach for these patients. This form of the statin brings about significantly greater reductions in total cholesterol, LDL-C, and non-HDL-C levels compared with nonencapsulated pravastatin, and it has a similar safety profile.

Because lipid abnormalities are common in patients taking protease inhibitors and there is an ongoing concern about potential drug interactions with statins, an enteric-coated formulation of pravastatin was compared with nonencapsulated pravastatin in HIV patients to assess LDL-C reductions after four weeks of therapy. The secondary endpoint of the study was to assess the biotransformation of pravastatin in the acid environment of the stomach and duodenum to the relatively inactive metabolite SQ 31.906 in both formulations of pravastatin after four weeks of therapy. It was hypothesized that the encapsulated formulation would offer better protection for the active drug and would result in enhanced bioavailability and greater efficacy.

A prospective, open-label, randomized crossover study enrolled 16 HIV-infected men who received a protease inhibitor and whose LDL-C levels exceeded the goals of the National Cholesterol Education Program. The patients were randomly assigned to receive standard tablets or encapsulated tablets (Capsule 00 Blue, Gallipot, Inc.; lactose monohydrate, Spectrum Chemical). They were instructed to take one tablet every evening for 28 days. After a 28-day washout period, the patients were switched to the alternative formulation.

Of the 16 patients who initially enrolled in the study, 12 completed the full courses of therapy. Encapsulated pravastatin produced significantly greater reductions in total cholesterol (-22%) than did the nonencapsulated type (-12%) and in LDL-C (-25% versus -13%, respectively).

The one-hour, post-dose ratio of plasma pravastatin to SQ 31.906 was higher with the encapsulated formulation (2.2 versus 1.1), demonstrating a reduction in the biotransformation of pravastatin canadian to SQ 31.906.

Beta-Blocker Exchange in Stable Heart Failure

Speaker: Andrea DiLenarda, MD, Director, Heart Failure Clinic, Ospedale di Cattinara, Triesta, Italy.

A subgroup analysis of data from the Carvedilol or Meto-prolol European Trial (COMET) suggests that (1) switching to a different beta blocker without downward dose titration is a practical, safe, and well-tolerated strategy for patients with clinically stable heart failure and (2) switching from metopro-101  (Novartis) to carvedilol (GlaxoSmithKline) results in fewer serious and heart failure-related events than switching to metoprolol while maintaining the survival benefit dvantage of carvedilol demonstrated in the original COMET study.

In the COMET study, a total of 3,029 patients with New York Heart Association class II-IV chronic heart failure were randomly selected to receive carvedilol, titrated to 25 mg daily, or metoprolol, titrated to 50 mg daily. The patients were monitored for 46 to 74 months. Produced a significant 17% reduction in cardiovascular mortality in patients with heart failure, compared with metoprolol.

Overall, 1,429 patients completed the COMET study on a regimen of the study’s beta blockers. Because the withdrawal of beta blockade may precipitate worsening heart failure and arrhythmias, all patients with stable heart failure who were taking the study medication in a blinded fashion were switched to open beta-blocker therapy. This was done without unblind-ing or downward dose titration at a dose equivalent to half the study dose of each patient. Thereafter, the investigators recommended titrating the dose upward to the maximum tolerated or to the targeted beta-blocker doses.

The physicians selected the beta blockers that they considered most appropriate. Of this group of patients, 92% were subsequently switched to a post-study beta blocker; 1,014 patients received carvedilol, 201 were given, and 102 received (Zebeta®, Lederle); 108 patients received no post-study beta blockers.

The rates of serious ADEs were lowest in patients who continued with canadian carvedilol (2.1%) or metoprolol (3.1%) or in patients who were switched from metoprolol to carvedilol therapy (3.1%). The rates were higher in patients who were switched from carvedilol to metoprolol (9.4%) or who discontinued beta blockers completely (11.1%). ADEs related to heart failure were more frequent in patients who switched from carvedilol to metoprolol (4.7%) than in those switching from canadian metoprolol to carvedilol (2.3%).

Intravenous Nesiritide in Patients with Congestive Heart Failure and Pulmonary Hypertension

Speaker: Teresa DeMarco, MD, Professor of Medicine and Director of the Heart Failure and Pulmonary Hypertension Program, University of California-San Francisco, San Francisco, California.

Nesiritide (Natrecor®, Scios, Inc.), a recombinant human B-type natriuretic peptide, has been shown to be highly effective, safe, and well tolerated in relieving moderate to severe pulmonary hypertension (PH) in patients with acute heart failure.
At the time of the presentation, 13 patients had enrolled in this study; the goal was 20 patients. PH was characterized by a mean pulmonary artery pressure above 25 mm Hg and a right atrial pressure above 7 mm Hg. The patients were referred for catheterization of the right side of the heart.

Nine patients had postcapillary PH, with a pulmonary capillary wedge pressure (PCWP) exceeding 15 mm Hg. Four patients had precapillary PH, with a PCWP below 15 mm Hg. In the postcapillary PH group, the mean left ventricular ejection fraction (LVEF) was 27 ± 18%; in the precapillary PH group, the LVEF was 63.6 ± 6%.

After a baseline right-heart catheterization, nesiritide was administered at 2 mcg/kg as an IV bolus, followed by a 30-minute infusion of 0.01 mcg/kg per minute. Subsequent hemodynamic evaluation of the right side of the heart was performed at 15 and 30 minutes.

At the baseline examination, in the group with postcapillary PH, the mean right atrial pressure was 10 ±1 mm Hg, the mean pulmonary artery pressure was 42 ± 7 mm Hg, and the PCWP was 25 ± 7 mm Hg. After the 30-minute infusion, nesiritide acutely and significantly decreased right atrial pressure by 52% and pulmonary artery pressure by 31%. The PCWP decreased by 46%, and pulmonary vascular resistance decreased by 33%.

There also was a significant decrease in arteriovenous oxygen difference (AVDO2) of 26%, which reflected improved cardiac performance. Cardiac output increased by 33%.
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For the few patients with precapillary PH at baseline, the mean right atrial pressure was 13 ±6 mm Hg, the mean pulmonary artery pressure was 43 ± 6 mm Hg, and the PCWP was 10 ± 4 mm Hg. After the 30-minute infusion of nesiritide, reductions in systemic pressure and systemic vascular resistance were similar to that observed in the precapillary PH group; however, no acute changes in right-sided heart hemo-dynamics, pulmonary vascular resistance, or AVDO2 were noted.

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