Coverage from the 57th Annual Scientific Session of the American College of Cardiology

Cardiology Review® OnlineMay 2008
Volume 25
Issue 5

ENHANCE: A call to ‘return to statins'

Adding ezetimibe to simvastatin does not slow the progression of atherosclerosis compared with simvastatin alone despite additional lowering of low-density lipoprotein (LDL) cholesterol and levels of high-sensitivity C-reactive protein (hs-CRP), said John Kastelein, MD, who reported the much-anticipated final results of ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression). The results of this study prompted a panel convened by the American College of Cardiology to issue a statement urging physicians to "go back to statins" when treating patients who have dyslipidemia.

The panel's spokesperson, Harlan Krumholz, MD, professor of medicine and epidemiology and public health (cardiology) at Yale University, New Haven, Connecticut, lamented the rapid uptake of ezetimibe in practice at the expense of statin prescriptions, even though no outcomes data have been reported with ezetimibe, and considerable data exist to prove the efficacy of statins in reducing mortality and cardiovascular end points. In fact, at nearly the same time that Dr Krumholz made his statements, AstraZeneca announced early termination of the JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) trial due to a clear efficacy advantage of rosuvastatin in patients with unremarkable LDL cholesterol levels but elevated hs-CRP levels.



In ENHANCE, 720 patients with familial hypercholesterolemia were randomized to 24 months of either simvastatin, 80 mg/day, plus placebo, or ezetimibe, 10 mg/day, added to the simvastatin. B-mode ultrasound imaging of the carotid and femoral arteries was used to assess intima-media thickness (IMT). More than 80% of the patients in each study group had previously been on a statin. The mean level of LDL cholesterol decreased from baseline by 16.5% or more in patients assigned to simvastatin-ezetimibe compared with those assigned to simvastatin monotherapy (< .01). The simvastatin-ezetimibe group also experienced an incremental 25.7% reduction in levels of hs-CRP compared with the simvastatin monotherapy group (< .01).


Despite the favorable changes in LDL cholesterol and hs-CRP values with the combination treatment, the change in the carotid artery IMT from baseline— the primary end point&mdash;differed by only .0053 mm between the 2 treatment groups; this finding was not significant (= .29).

Both regimens were well-tolerated and there were no safety issues with ezetimibe, said Dr Kastelein, professor of medicine and chairman of the department of vascular medicine, Academic Medical Centre of the University of Amsterdam, The Netherlands.

In exploring potential reasons for the lack of additional benefit of ezetimibe, Dr Kastelein rejected the notion that the measurement technique was not accurate enough to reflect changes in atherosclerotic burden, noting the close relationship between IMT thickness and cardiovascular risk observed in other large studies. He hypothesized that the high level of pretreatment with statins may have rendered the study population at too low of a risk to detect changes, "which would limit the ability to detect a differential response."

By 2006, 15% of all prescriptions in the United States for lipid-lowering medicines included ezetimibe, noted Dr Krumholz, at a time when statin prescriptions declined.

"[Enhance] provides us no clinical evidence to support use of [ezetimibe], and it moves us to more uncertainty about the benefit of this drug. The principal harm is that [use of ezetimibe] drains precious resources from our health care system," said Dr Krumholz.

"The strongest recommendation we can make is to turn back to statins," he said. "We need to go back to what works…let's stay with the evidence."

New study supports paradigm shift in hypertension management

Hypertension management may undergo a paradigm shift based on the results of a new study in which combination therapy improved blood pressure control and the combination of an angiotensin-converting enzyme (ACE) inhibitor/calcium channel blocker (CCB) was superior to an ACE inhibitor/diuretic on cardiovascular outcomes in patients with high-risk hypertension. Current guidelines recommend initiating treatment with monotherapy, preferably with a diuretic.

"The data are compelling that the standard care is going to change. You're going to be using more combination therapy and specifically the combination that was superior in this trial—an ACE inhibitor/CCB," said Kenneth Jamerson, MD, lead investigator of a trial known as ACCOMPLISH (Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension) and professor of internal medicine, University of Michigan, Ann Arbor. ACCOMPLISH included 11,462 patients who had a systolic blood pressure of at least 160 mm Hg or were on antihypertensive therapy. To be eligible, patients had to have evidence of cardiovascular disease, renal disease, or target organ damage.

Despite nearly all of the trial participants having been previously treated for hypertension, their mean systolic blood pressure at study entry was 145.4 mm Hg. Almost three fourths (74%) had been treated with 2 or more antihypertensive agents.

Patients were randomized to either amlodipine 5 mg/benazepril 20 mg or benazepril 20 mg/hydrochlorothiazide 12.5 mg. Patients assigned to amlodipine/benazepril could be uptitrated to 10 mg/40 mg and those assigned to benazepril/hydrochlorothiazide could be uptitrated to 40 mg/25 mg to achieve a blood pressure less than 140/90 mm Hg (or <130/80 mm Hg in patients with diabetes or renal insufficiency).

Beta blockers, alpha blockers, clonidine, and loop diuretics could be added, if needed, to achieve blood pressure goals. At the final office visit, which occurred at 30 months, the mean systolic blood pressure was 130 mm Hg in the group assigned to benazepril/hydrochlorothiazide and 129.3 mm Hg in the group assigned to amlodipine/ benazepril.



Hypertension control improved from 37% before study entry to 80% at 30 months. Half of the study participants had their blood pressure controlled with just 1 tablet, said Dr Jamerson. At a mean follow-up of 39 months, amlodipine/ benazepril was associated with a 20% reduction (< .002) in the occurrence of the primary end point, a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for angina, coronary revascularization procedure, and resuscitation from sudden death. When the analysis was confined to only "hard" cardiovascular end points (cardiovascular death, stroke, and MI), participants randomized to amlodipine/benazepril had a 21% reduction (= .007) compared with subjects randomized to benazepril/ hydrochlorothiazide.

"It looks like the conventional wisdom of having a diuretic in the initial management of hypertension has to be revisited in future guidelines, and if the results are driven by the calcium channel blocking drug, it also puts to rest all the unsettled issues in the past about the dangers of CCBs on bleeding, cancer, and dementia," said C. Venkata Ram, MD, professor of internal medicine, University of Texas Southwestern Medical Center, and director of the Texas Blood Pressure Institute, Dallas. Mechanistic studies conducted in animals support an additive vasodilating effect and enhanced nitric oxide bioavailability by combining a CCB and ACE inhibitor, said Dr Jamerson.

Survival similar with PCI and CABG surgery for left main disease

Percutaneous coronary intervention (PCI) may offer the same survival benefit as coronary artery bypass graft (CABG) surgery in patients with unprotected left main disease, according to Seung-Jung Park, MD, director of interventional cardiology, Asian Medical Center, Seoul, Korea.

"Because the recommendation for surgery for left main disease is based mostly on survival benefit, the lack of a statistically significant difference in mortality may support PCI as an alternative to bypass surgery," said Dr Park.

He reported the results of the Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization (MAIN-COMPARE) study, which analyzed data from 2,240 patients with unprotected left main disease with stenosis greater than 50% who were treated at 12 Korean medical centers.

Bare-metal stents were used in 318 patients, drug-eluting stents in 784, and 1,138 patients underwent CABG surgery. Outcome measures were compared during the first 3 years after treatment and included death; a composite outcome of death, Q-wave myocardial infarction, or stroke; and target-vessel revascularization.

There was no significant difference between the PCI and CABG surgery groups in the risk of death (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.77-1.80) or the risk of the composite outcome (HR, 1.10; 95% CI, 0.75-1.62); however, the rates of target-vessel revascularization were significantly higher for PCI patients (HR, 4.76; 95% CI, 2.9-8.11). The risk of revascularization specifically for restenosis of the left main coronary artery was also significantly higher in the PCI group (HR, 2.72; 95% CI, 1.51-4.91).

"The only difference was between the type of stents. Drug-eluting stents compared with bare-metal stents may reduce the number of revascularizations," said Dr Park. Patients receiving drug-eluting stents were 6 times more likely to require revascularization than CABG surgery patients, whereas those receiving bare-metal stents were 11 times more likely to require revascularization.

Compared with the CABG surgery group, the risk of death (HR, 1.04) and the risk of the composite outcome (HR, 0.86) was similar among the patients receiving bare-metal stents. There was a nonsignificant trend toward higher rates of death (HR, 1.36) and the composite outcome (HR, 1.40) among the patients receiving drug-eluting stents compared with CABG surgery.

Of the study patients, 65% received a single stent. "For left main disease, even for true angiographic bilateral lesions, we prefer a single crossover stent rather than a double stent," said Dr. Park.

Because physicians in different geographical locations have varying skill levels in treating unprotected left main disease with PCI, more globalized, randomized trial results are needed, Dr Park said. "Unprotected left main stenting should not be attempted in clinical practice before the physician has achieved specialized experiences," he noted.

According to E. Murat Tuzcu, MD, director of the Intravascular Ultrasound Laboratory and an interventional cardiologist at the Cleveland Clinic, PCI is almost always used to treat left main disease in Korea whereas only 1 in 5 such cases in the United States are treated with PCI. Results of the SYNTAX (Synergy between percutaneous coronary intervention with Taxus and cardiac surgery) study, in which 1,500 patients with complex coronary disease (3-vessel disease, left main disease, or left main equivalent) are being randomized to PCI or CABG surgery will provide more information on the worldwide experience using PCI in left main disease, he said. Results of SYNTAX are expected in September.

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