A new class of lipid-lowering agents is proving to be effective for preventing both first and second heart attacks in patients with hypercholesterolemia. These agents reduce cholesterol levels by inhibiting the activity of the hepatic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Blocking this enzyme increases the hepatic production of cholesterol receptors, and these receptors, in turn, pull cholesterol out of the bloodstream. In addition to reducing serum cholesterol, HMG-CoA reductase inhibitors have been shown to reduce levels of low-density lipoprotein (LDL) cholesterol, triglycerides, and lipoprotein(a) (an atherogenic and thrombogenic blood component), and to increase levels of high-density lipoprotein (HDL) cholesterol.
There are five HMG-CoA reductase inhibitors available on prescription in the US — lovastatin (Mevacor/Merck), simvastatin (Zocor/Merck), pravastatin (Pravachol/Bristol- Myers Squibb), and fluvastatin (Lescol/Sandoz) — and there are several more under clinical investigation, including one in late-stage trials at Warner-Lambert. Also known as “statins,” these agents slow the progression of coronary artery disease (CAD) and have actually been shown to induce regression of atherosclerotic lesions in CAD patients. They reduce the incidence of death from coronary causes and death from any cause in men with established coronary artery disease. There is also evidence that the statins may affect coronary vasculopathy by a mechanism independent of cholesterol lowering, possibly associated with the immune system. The more lipophilic (fat loving) statins have been associated with some skeletal muscle complaints (myositis, rhabdomyolysis), but most of the side effects reported in clinical trials have been mild and tolerable (headache, abdominal pain, constipation, flatulence, and diarrhea).
Cardiovascular disease afflicts nearly 60 million Americans and leads to almost half of all deaths, yet only about a quarter of patients with angina or a previous myocardial infarction (MI) are taking a drug to reduce cholesterol levels. With annual sales worldwide of more than $4 billion and an enormous potential market, HMG-CoA reductase inhibitors could become one of the most successful classes of pharmaceuticals ever developed.
Preventing Second Heart Attacks with Simvastatin
The first of the major clinical trials to document the beneficial effects of the statins on mortality from heart disease was the Scandinavian Simvastatin Survival Study. In this five-year, multicenter trial involving 4,444 middle aged men with hypercholesterolemia and established CAD, simvastatin in a dose of 20-40 mg per day reduced the overall risk of heart attack (fatal and nonfatal) by 37%. Benefits were apparent within about one year of initiation of therapy, and by two years the risk of coronary artery disease death was reduced by 46%. Although the study focused on preventing second heart attacks, the investigators noted that simvastatin also reduced the risk of undergoing myocardial revascularization procedures by 37% and slightly reduced fatal and nonfatal cerebrovascular events. (Scandinavian Simvastatin Survival Study Group (4S).
According to Merck, the cost of the drug administered to study participants ($11.5 million) was only partially offset by the savings in hospitalization ($8 million) — but there are 75 more people alive today who would otherwise have succumbed to heart disease.
Preventing First Heart Attacks with Pravastatin
If reducing cholesterol levels can increase survival in patients with coronary artery disease, will cholesterol reduction increase survival in hypercholesterolemic subjects without any signs of CAD? Scottish researchers have reported that reducing cholesterol levels in otherwise healthy men with hypercholesterolemia can indeed reduce mortality from coronary artery disease. In the West of Scotland Coronary Prevention Study, the HMG-CoA reductase inhibitor pravastatin (Pravachol/Bristol-Myers Squibb) was found to be effective for preventing first heart attacks in men apparently free of coronary disease. Participants in this placebo-controlled trial were 6,595 middle-aged men (45-64 years old) in apparent good health but with LDL cholesterol levels of 155-232 mg/dL (4.0-6.0 mmol/L), the highest quartile of the range found in the British population. (In the US, approximately 25% of the adult male population has LDL cholesterol levels above 155 mg/dL.)
Compared with placebo, pravastatin 40 mg/day lowered plasma cholesterol levels by 20%, low-density lipoprotein cholesterol by 26%, and triglycerides by 12%, and increased levels of HDL cholesterol by 5%. During five-year follow-up, pravastatin significantly reduced the rate of fatal and nonfatal coronary events (by 31%), death from all cardiovascular causes (by 32%), and overall mortality (by 22%). Risk reduction was independent of age and smoking status, and beneficial effects were seen within six months of initiation of therapy. As in the simvastatin study, coronary angiography and revascularization were significantly reduced in the treated group. When subjects were grouped based on lipid levels at baseline, coronary risk was related to higher plasma LDL cholesterol and triglyceride levels (levels above the median values) and lower HDL cholesterol levels (below the median value). Plasma cholesterol was not a significant factor.
Pravastatin is unique among the HMG-CoA inhibitors in that it is hydrophilic and so skeletal muscle side effects are not the problem they are with lipophilic agents. As with other studies, pravastatin did not cause myopathy and had no effect on liver function. Therapy was well tolerated and withdrawals from the pravastatin group were no more frequent than from the placebo group. According to the investigators, “reducing cholesterol levels with pravastatin reduces the risk of coronary events in asymptomatic subjects with hypercholesterolemia.” They estimated that if 1000 men with hypercholesterolemia and no evidence of previous myocardial infarction were treated with pravastatin for five years, there would be 20 fewer nonfatal MIs, seven fewer deaths from cardiovascular causes and two fewer deaths from other causes than would be expected in the absence of statin therapy. Bristol-Myers spent $30 million on the study, but it remains to be seen how the cost of treatment balances the cost of disease.
Heart Transplantation: Adding Pravastatin to the Drug Regimen
Survival following heart transplantation has increased dramatically in recent years. For patients today who can afford the high cost of transplantation and are lucky enough to obtain a donor heart, survival rates following surgery are about 85% after one year and 70% after five years. The three factors limiting survival are rejection and infection during the first year after transplantation, and accelerated CAD. Rejection is controlled primarily with the immunosuppressant cyclosporine, infection with a range of antimicrobials, and CAD with drugs to reduce hypercholesterolemia.
Cyclosporine by itself deserves much of the credit for prolonging post-transplantation survival. According to editorialists Valantine and Schroeder in New England Journal of Medicine, at least 60% of patients can be maintained on cyclosporine plus a second immunosuppressant (azathioprine), with corticosteroids added when rejection occurs. For patients resistant to corticosteroids, antilymphocyte antibodies can be administered, although this will increase the risk of infection and lymphoma. The most promising drugs under investigation for preventing transplant rejection are those that inhibit the metabolism, proliferation, or activity of the T-lymphocytes involved in the rejection mechanism.
To reduce the risks associated with cyclosporine therapy (the drug is nephrotoxic), investigators are coadministering the drug with an agent that delays the metabolism of cyclosporine, effectively extending the half-life and reducing the dose of cyclosporine required to maintain therapeutic blood levels. Two cyclosporine-sparing agents under investigation — diltiazem and ketoconazole — are known to bind hepatic cytochrome oxidase and inhibit cyclosporine metabolism. In a study of diltiazem coadministered with cyclosporine after heart transplantation, Valantine et al found that patients in the diltiazem group had reduced rates of coronary artery narrowing during the first year, a decrease in the number of patients dying from coronary artery disease in the transplants, and a marked improvement in overall survival. Diltiazem also reduced systemic blood pressure, improved renal function, and slowed the development of hypercholesterolemia.
Ketoconazole is another cyclosporine-sparing agent that can reduce the dose required to maintain adequate immunosuppression. In their study of 43 cardiac transplant patients, Keogh et al found that early administration of low-dose ketoconazole (200 mg per day) reduced the cyclosporine dose by 62% at one week and 80% at one year (as compared with controls). Moreover, ketoconazole reduced the rate of rejection and the incidence of infection. Since ketoconazole is an antifungal, the dramatic reduction in fungal infections observed in treated patients was expected. But treated patients showed reductions in all types of infection. Since ketoconazole also has some activity against certain bacteria and viruses (for example, Staphylococcus epidermidis, Nocardia, and herpes simplex viruses 1 and 2), the overall reduction in infectious disease is probably due to ketoconazole’s broad antimicrobial action. The reduction in infection could also reflect reduced immunosuppression because of the lower dose of cyclosporine needed. The investigators estimated that ketoconazole therapy resulted in cost savings per patient of $5,200 in the first year of therapy and about $3,920 in each subsequent year. This estimate represents only the cost of drugs, not the savings from reduced rates of rejection and infection.
Another important cause of morbidity following heart transplantation is accelerated coronary artery disease. Hypercholesterolemia is common after transplantation, affecting 60-80% of recipients and causing coronary vasculopathy in the transplants. Kobashigawa et al reported that early use of pravastatin after cardiac transplantation safely lowers cholesterol levels, reduces the incidence of CAD, decreases the incidence of major rejection (accompanied by hemodynamic compromise), improves one-year survival, and reduces the development of coronary vasculopathy (as diagnosed by coronary angiography, intracoronary ultrasonography, or at autopsy). The investigators followed 47 transplant patients given pravastatin 20-40 mg/day and 50 transplant patients who did not receive pravastatin (to serve as controls). Although pravastatin did not prevent rejection, it delayed the onset of rejection and thus improved first-year survival. The beneficial effects may result directly from the reduction in cholesterol levels, or may be due to the effects of pravastatin on the immune system (the drug suppresses natural killer cells). There may be a synergistic effect between pravastatin and cyclosporine, since pravastatin does not cause immunosuppression in the absence of cyclosporine (i.e. in patients who do not have transplants).
Infection, rejection, and accelerated CAD in the transplanted heart are all interrelated. For example, the most common cause of infection following transplantation is cytomegalovirus, and this virus not only increases morbidity but also predisposes patients to rejection and coronary artery disease of their transplants. The antiviral ganciclovir in combination with cytomegalovirus hyperimmune globulin provides the best prophylaxis against cytomegalovirus infection, and also prevents fungal infections, reduces the incidence of acute rejection, and has the potential to protect against CAD in transplants. Ketoconazole protects against a broad range of fungal, bacterial and viral infections, and reduces the incidence of transplant rejection. And pravastatin reduces coronary artery disease and protects against rejection. The optimal drug regimen following heart transplantation may turn out to be cyclosporine, ketoconazole, and pravastatin, with ganciclovir plus cytomegalovirus hyperimmune globulin for preventing viral infection. What remains to be seen is what adverse effects these drugs have on each other and on the patient.