Data do not back up combination therapy for CHD

Such practice puts the patient at unnecessary risk and may deny the benefit of therapy with a proven dose of statin monotherapy.

Patients with established coronary heart disease (myocardial infarction, stable angina and documented coronary artery disease) and patients with diabetes or peripheral, cerebral and carotid vascular disease, or hypertension, are at high risk for developing myocardial infarction, stroke, sudden ischemic death, and unstable angina.

Statin therapy

High levels of total cholesterol or LDL and low levels of HDL are associated with adverse clinical cardiovascular outcomes. Several large, placebo-controlled trials have shown that treatment with a fixed, intermediate dose of statins reduces cardiovascular mortality and morbidity and total mortality in the majority of the trials. All these trials included those patients with established CHD.

UdhoThadani

Doses of statins used in these trials have been simvastatin (Zocor, Merck; 20 mg to 40 mg daily) in the Scandinavian Simvastatin Survival Study, pravastatin (40 mg daily) in the Cholesterol and Recurrent Event and LIPID Trials and simvastatin (40 mg daily) in the Heart Protection Study (HPS). With the exception of HPS, patients studied had LDL levels >130 mg/dL; in the HPS, total cholesterol values >135 mg/dL were required for inclusion in the trial and patients entered the trial irrespective of baseline LDL values. None of the trials required titration of the dose of the statin to achieve a desired total cholesterol or LDL goal.

In contrast to these placebo-controlled trials, the Treating to New Target trial compared fixed, low-dose atorvastatin (Lipitor, Pfizer; 10 mg daily) to a high dose atorvastatin (80 mg daily) treatment in patients with stable CHD. There was a significant reduction in the rate of primary endpoint (death from CHD, nonfatal MI, fatal or nonfatal stroke, resuscitation after cardiac arrest) but there was no difference in total mortality. An increase in noncardiovascular deaths with high dose compared to low dose atorvastatin treatment was observed. Furthermore, liver function test abnormalities were more frequently observed in the high dose group.

In the Incremental Decrease in Endpoints through Aggressive Lipid Lowering study, treatment with high dose atorvastatin (80 mg daily) was not superior to treatment with an intermediate dose of simvastatin (20 to 40 mg daily) with regards to total mortality or major coronary events including death, hospitalization for acute MI or cardiac arrest. More patients discontinued high dose atorvastatin therapy, experienced myalgia and had elevated liver function tests compared to simvastatin therapy.

Treating patients with ACS

In patients hospitalized for acute coronary syndrome, treatment with a fixed high dose of atorvastatin (80 mg daily) was shown to be superior to intermediate dose of pravastatin (40 mg daily), in the TIMI-22 trial. In this trial an early benefit on the combined endpoint – all-cause mortality, MI, unstable angina requiring hospitalization, revascularization or stroke – was seen in the atorvastatin 80 mg group. The positive outcome was primarily driven by nondeath related endpoints.

However, in another study called the A to Z Trial, no early benefit was observed with high dose simvastatin (80 mg daily) compared to no treatment for four months followed by intermediate dose simvastatin therapy in patients with ACS.

Despite this limited and variable outcome data on the dose effects of statins, current American Heart Association, American College of Cardiology and National Cholesterol Education Program guidelines recommend aggressive pharmacotherapy for dyslipidemia in CHD patients to a LDL goal of less that 100 mg/dL and preferably less than 70 mg/dL. If this goal is not reached with statin monotherapy, current recommendations are to add a fibrate, nicotinic acid or ezetimibe.

In my opinion, there are several issues of concern with such an approach.

Combination therapy

There are no published trials showing that the combination therapy is superior to statin monotherapy with regards to clinical outcomes.

Combination treatment of statins and fibrates, and to a certain extent nicotinic acid, increases the risk of adverse side effects especially myalgia and rhabdomyolysis.

One trial of fibrates with gemfibrozil (VA-HIT Trial) in male patients with a previous MI and low HDL levels of <40 mg/dL there was an improvement in clinical cardiovascular outcomes. Other trials with fibrates, including a recent trial, the FIELD Study, with fenofibrate in patients with diabetes, failed to show any improvement in cardiovascular outcomes.

Combination of a statin, atorvastatin, plus torcetrapib (Pfizer), a cholesteryl ester transfer protein inhibitor, was shown to increase cardiovascular events and mortality compared to treatment with atorvastatin alone in the Illuminate trial. This imminent trial was prematurely stopped by the data safety monitoring committee in December 2006. There was a great hype about torcetrapib as in previous studies it was shown to raise HDL levels and slow the progression of coronary atherosclerosis.

Earlier small trials with nicotinic acid have shown a favorable trend in clinical outcomes, but worsening of diabetes remains a concern. Outcome trials of statin and nicotinic acid combination are lacking at the present time. The ongoing Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes trial is a multicenter, randomized, double-blind, parallel group, controlled clinical trial in which superiority of extended-release niacin plus simvastatin is being compared to simvastatin treatment alone. It remains to be shown that this combination is superior to simvastatin therapy alone, which has been shown to improve cardiovascular outcomes and total mortality in patients with CHD.

Current FDA labeling recommends lowering the dose of a statin to a very low dose (10 to 20 mg daily) when using combination treatment of a statin and especially a fibrate in order to avoid the risk of rhabdomyolysis. This approach is not being followed by many physicians and may put the patients at unnecessary risk. If the recommendation is followed, it may lead to use of a much lower dose of statin than that shown to improve outcomes in the large randomized clinical trials. This approach denies patients of an effective and proven therapy.

Combination of a statin plus ezetimibe or more potent statin monotherapy such as rosuvastatin (Crestor, AstraZeneca) does lower LDL to a greater extent but outcome trials are lacking.

There is no outcome data on the combination therapy of simvastatin plus fish oil, which lowers triglyceride levels.

For patients with CHD and very high triglyceride levels (>500 mg/dL) initial treatment of choice is a fibrate after dietary changes. Once triglyceride values are below 500 mg/dL, the role of statins in this group of patients remains unknown.

Therefore, in the absence of outcome data showing superiority of combination therapy together with an increase in the incidence of adverse events, one cannot recommend routine use of combination therapy in order to achieve recommended LDL and HDL goals. Such practice puts the patient at unnecessary risk and may deny the benefit of effective therapy with a proven dose of intermediate to high dose statin monotherapy.

A rational approach

From the available data a rational approach for patients with established CHD or CHD equivalents is for them to receive fixed-dose treatment with an intermediate dose of a statin such as pravastatin or simvastatin 40 mg once daily when LDL levels are >130 mg/dL or simvastatin 40 mg daily irrespective of LDL levels as long as the total cholesterol level is >135 mg/dL. If tolerated, such an approach would benefit the majority of patients and reduce the economic burden associated with dose titration and combination therapy. High dose atorvastatin (80 mg daily) is an alternative but because of the lack of effect on total mortality compared to low dose atorvastatin (10 mg daily) and the availability of cheaper generic versions of statin, this alternative approach remains open to questions.

In men with CHD and low HDL levels (<40 mg/dL) and high triglyceride values, gemfibrozil monotherapy may be used rather than a statin. However, the combination of gemfibrozil or another fibrate plus a statin is not indicated in the absence of outcome data.

For patients with ACS, high dose atorvastatin (80 mg daily) may be used instead of treatment with an intermediate dose of other statins (pravastatin or simvastatin) but this is based on only one outcome trial. More trials are needed before adopting high dose treatment in all patients with ACS.

Large outcome trials with combinations of lipid modifying agents comparing monotherapy with statins are needed before one can justify routine use of combination therapy to achieve the recommended LDL goals.

Udho Thadani, MD, MRCP, FACC, FAHA, is Professor Emeritus (Active) of Medicine, University of Oklahoma, Consultant Cardiologist, Oklahoma University Medical Center and VA Medical Center Oklahoma City, Oklahoma. He is a member of the Cardiovascular Pharmacology Section of Today in Cardiology’s Editorial Board.

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