Simon F. Shakar

Drug Therapy in the Heart Transplant Recipient Part II: Immunosuppressive Drugs

Received March 16, 2004; revision received July 23, 2004; accepted September 30, 2004. Part I of this series describes the mechanisms and types of rejection and the intravenous immunosuppressive drugs commonly used for induction or antirejection therapy. In this article, we review the commonly used oral immunosuppressive drugs. Intravenous corticosteroid methylprednisolone is included in the discussion of corticosteroids. Table 1 gives trade names, pharmacology, necessary adjustments for renal or hepatic dysfunction, and dosing and general monitoring guidelines for drugs described in this section. Table 2 lists the major adverse effects of immunosuppressive drugs described in Parts I and II of this review and provides an estimate of their relative frequency. View this table: TABLE 1. Commonly Used Oral (and Intravenous) Immunosuppressive Drugs View this table: TABLE 2. Major Adverse Effects of Immunosuppressive Drugs Steroids, among the first immunosuppressive agents used in clinical transplantation, have remained an important component of induction, maintenance, and rejection regimens. ### Mechanism of Action Glucocorticoids are potent immunosuppressive and antiinflammatory agents (the Figure). They diffuse freely across cell membranes and bind to high-affinity cytoplasmic glucocorticoid receptors. The glucocorticoid receptor–steroid complex translocates to the nucleus, where it binds to a glucocorticoid response element within the DNA.1 The glucocorticoid receptor–steroid complex may also bind to other regulatory elements, inhibiting their binding to DNA. Both actions cause transcriptional regulation, thereby altering the expression of genes involved in immune and inflammatory response. Glucocorticoids affect the number, distribution, and function of all types of leukocytes (T and B lymphocytes, granulocytes, macrophages, and monocytes), as well as endothelial cells.2 The major effect on lymphocytes appears to be mediated by inhibition of 2 transcription factors, activator protein-1 and nuclear factor (NF) κ-B.3,4 This affects the expression of a number of genes, including those for growth factors, cytokines, CD40 ligand, GM-CSF, and adhesion and myosin heavy chain molecules.2 In nonlymphoid …

Combined oral positive inotropic and beta-blocker therapy for treatment of refractory class IV heart failure

OBJECTIVES We sought to assess the effects of combined oral positive inotropic and beta-blocker therapy in patients with severe heart failure. BACKGROUND Patients with severe, class IV heart failure who receive standard medical therapy exhibit a 1-year mortality rate >50%. Moreover, such patients generally do not tolerate beta-blockade, a promising new therapy for chronic heart failure. Positive inotropes, including phosphodiesterase inhibitors, are associated with increased mortality when administered over the long term in these patients. The addition of a beta-blocker to positive inotropic therapy might attenuate this adverse effect, although long-term oral inotropic therapy might serve as a bridge to beta-blockade. METHODS Thirty patients with severe heart failure (left ventricular ejection fraction [LVEF] 17.2+/-1.2%, cardiac index 1.6+/-0.1 liter/min per m2) were treated with the combination of oral enoximone (a phosphodiesterase inhibitor) and oral metoprolol at two institutions. Enoximone was given at a dose of < or = 1 mg/kg body weight three times a day. After clinical stabilization, metoprolol was initiated at 6.25 mg twice a day and slowly titrated up to a target dose of 100 to 200 mg/day. RESULTS Ninety-six percent of the patients tolerated enoximone, whereas 80% tolerated the addition of metoprolol. The mean duration of combination therapy was 9.4+/-1.8 months. The mean length of follow-up was 20.9+/-3.9 months. Of the 23 patients receiving the combination therapy, 48% were weaned off enoximone over the long term. The LVEF increased significantly, from 17.7+/-1.6% to 27.6+/-3.4% (p=0.01), whereas the New York Heart Association functional class improved from 4+/-0 to 2.8+/-0.1 (p=0.0001). The number of hospital admissions tended to decrease during therapy (p=0.06). The estimated probability of survival at 1 year was 81+/-9%. Heart transplantation was performed successfully in nine patients (30%). CONCLUSIONS Combination therapy with a positive inotrope and a beta-blocker appears to be useful in the treatment of severe, class IV heart failure. It may be used as a palliative measure when transplantation is not an option or as a bridge to heart transplantation. Further study of this form of combined therapy is warranted.

Drug therapy in the heart transplant recipient: part I: cardiac rejection and immunosuppressive drugs.

Survival after heart transplantation has improved considerably over the past 20 years. Half of all patients now live >9 years, and ≈25% live ≥17 years.1 Currently, ≈20 000 heart transplant recipients live in the United States.2 Improved longevity means prolonged immunosuppression and the concomitant use of drugs to prevent or treat the long-term complications of immunosuppressive agents, such as infection, obesity, hypertension, hyperlipidemia, renal insufficiency, diabetes, osteoporosis, gout, and malignancies. In 1989, heart transplant recipients surviving 1 year were reported to be taking 16±6 drug doses per day (prescription and nonprescription).3 In 2001, heart transplant recipients surviving an average of 76 months were taking 7 prescription drugs (range, 2 to 14), along with a number of nonprescription drugs.4 Thus, despite prolonged survival, heart transplant recipients continue to take multiple medications. With the large number of heart transplant recipients in the community and the increasing number of immunosuppressive and nonimmunosuppressive drugs used by these patients, it is important that the general cardiologist understand these drugs, their side effects, and the very real potential for drug–drug interactions. These interactions may result in adverse events caused by supratherapeutic and subtherapeutic drug concentrations. In this series, we review mechanisms and types of rejection, immunosuppressive drugs commonly used in the heart transplant recipient, common medical problems after transplantation, and clinically significant drug–drug interactions. A brief review of known immunologic mechanisms leading to graft rejection highlights the action of individual immunosuppressive drugs, as well as the rationale for combination therapy5–8 (Figure). The rejection of a transplanted organ is primarily a T-lymphocyte (T-cell)–mediated event, although humoral (B-cell) responses also contribute. The exception is hyperacute rejection, which occurs when preformed antibodies to human leukocyte antigens (HLA) result in an immediate and catastrophic rejection. Immune recognition of donor antigens that differ from those of …

Drug Therapy in the Heart Transplant Recipient Part III: Common Medical Problems

Continued improvement in the long-term survival of heart transplant recipients has resulted in a population of patients with prolonged exposure to immunosuppressive drugs.1 This exposure, coupled with the increasing age of recipients, has resulted in an impressive prevalence of comorbidities in these patients. Indeed, by 5 years after transplantation, 95% of recipients have hypertension, 81% have hyperlipidemia, and 32% have diabetes.1 In addition, 25% to 50% have coronary allograft vasculopathy (CAV), and up to 33% have chronic renal insufficiency.2–5 As more drugs are developed to both prevent and treat these problems and common infectious complications after transplantation, it is likely that the heart transplant recipient will be taking an increasing number of drugs. Because standard immunosuppressive drugs have a high potential for drug–drug interactions, the heart transplant recipient is subject to an enormous risk for drug–drug interactions. In this article, we briefly review common medical problems in heart transplant recipients that are routinely addressed with drug therapy. In Part IV of this series, we provide specific details of known important and common drug–drug interactions, along with recommendations for management.

Left ventricular assist device as bridge to transplantation does not adversely affect one-year heart transplantation survival.

OBJECTIVE Left ventricular assist devices are increasingly used as a bridge to transplantation. It remains unclear whether the use of pretransplant left ventricular assist devices adversely affects short-term survival after cardiac transplantation. METHODS A retrospective review of 317 consecutive patients undergoing cardiac transplantation at an academic center between 1986 and 2006 was undertaken. Left ventricular assist devices were used pretransplant in 23 of these 317 patients, and 294 patients did not require left ventricular assist device support. Patients with a left ventricular assist device were supported with a Heartmate VE or Heartmate XVE (Thoratec Corp, Pleasanton, Calif). Kaplan-Meier survival estimates were compared between the left ventricular assist device group and the non-left ventricular assist device group using the log-rank test. In addition, occurrence of death was analyzed between the 2 groups with a chi-square analysis. The results are expressed as 1-year survival with 95% confidence intervals in parentheses. RESULTS The 1-year survival for all 317 patients was 0.86 (0.82-0.90). The patient survival for the group without a left ventricular assist device before cardiac transplant was 0.87 (0.83-0.90), and the survival for the group with a left ventricular assist device as bridge to transplantation was 0.83 (0.67-0.98; P = .77). For the deaths that occurred in all 317 patients, 19% of the patients without left ventricular assist devices died within 30 days of transplant, whereas 80% of the patients with left ventricular assist devices died within 30 days of transplant (P < .01). CONCLUSION When used as a bridge to transplantation, left ventricular assist devices do not compromise 1-year survival after cardiac transplantation. Of the patients who die after transplantation, patients bridged with left ventricular assist devices are at higher risk for death within 30 days of transplant. These data suggest that left ventricular assist devices as a bridge to transplantation should be considered for appropriately selected patients awaiting cardiac transplantation.

Editorial commentary: "All that glitters is not gold".

Solid-phase immunoassays to assess human leukocyte antigens (HLAs) and anti-HLA antibodies are a major advance in transplantation immunology. Currently, they still have some limitations such as the inability to distinguish clinically significant antibodies from natural antibodies. Complementary information derived from older techniques is still useful for the complete assessment of some complex patients with anti-HLA antibodies before and after cardiac transplantation. More research and refinement of the current technology (intact HLA molecules on beads, etc.) would improve the immunologic risk assessment of such patients. The introduction of solid-phase immunoassays to assess human leukocyte antigens (HLAs) and anti-HLA antibodies was a major advance in the field of transplantation immunology. The ability to identify specific anti-HLA antibodies has allowed “virtual cross-matching,” the process of crossmatching a recipient’s anti-HLA antibodies to the HLAs of the donor. Virtual cross-matching allows for more timely allocation of organs because it saves the time needed to transport donor tissue to the immunology laboratory and the time to perform the prospective cross-match, thus improving utilization of donor organs. The ability to identify specific anti-HLA antibodies has allowed studies of the effect of anti-donor antibodies on long-term outcomes. Many transplant centers now perform HLA matching solely using the new technology and have dropped older membrane-based techniques such as complement-dependent cytotoxicity–anti-human globulin (CDC-AHG) and flow cytometry. However, despite the power of these new techniques, many clinical issues remain unresolved, including the concern that the newer techniques may detect antiHLA antibodies that bind antigen but cannot fix complement and thus would not result in rejection. In this issue of the Journal of Heart and Lung Transplantation, Nikaein et al make this concern a reality. They describe 5 of 14 patients who received ventricular assist devices (VAD) as a bridge to transplantation who were

Post-pericardial injury syndrome after continuous-flow ventricular assistance

We present a patient with post-pericardial injury syndrome (PPIS) that occurred after implantation of a continuous-flow left ventricular assistance device. Evidence supporting the diagnosis includes radiographic, electrocardiographic, and serologic markers. Recognition of this syndrome is important in this patient population to appropriately treat the patient as well as prevent unnecessary testing and prolonged hospitalization.

Myocardial protection in sepsis

Sepsis with myocardial dysfunction is seen commonly. Beta-blockers have been used successfully to treat chronic heart failure based on the premise that chronically elevated adrenergic drive is detrimental to the myocardium. However, recent reports on the acute use of beta-blockers in situations with potential hemodynamic compromise have shown the risks associated with this approach. In critical situations, the main effect of adrenergic activation is to support cardiovascular function. Caution should be exercised in designing studies to assess beta-blockers in septic patients.