SNOWMASS, COLO. — Administering an ACE inhibitor or carvedilol in cancer patients prior to high-dose chemotherapy is an excellent strategy for preventing chemotherapy-induced cardiomyopathy.
Chemotherapy-induced cardiomyopathy (CIC) is a far more common problem than most nononcologists appreciate, occurring in at least a quarter of patients on some widely prescribed regimens. Affected patients are not only exposed to the morbidity and mortality of heart failure, but their cancer therapy often has to be curtailed because of their cardiac impairment.
So rather than waiting for CIC to occur and then scrambling treat it, why not prevent it?, asked Dr. John S. Schroeder, professor of medicine at Stanford (Calif.) University, asked at a conference sponsored by the Society for Cardiovascular Angiography and Interventions.
He cited two randomized trials that have paved the way. In one, Dr. Nihat Kalay and colleagues at Erciyes University, Kayseri, Turkey, randomized 50 cancer patients slated to start notoriously cardiotoxic anthracycline chemotherapy to carvedilol (Coreg) at 12.5 mg once daily or placebo. At 6 months' follow-up, the mean left ventricular ejection fraction (EF) in the carvedilol group was essentially unchanged from the 70% baseline figure, while in the control group it fell from 69% to 52%.
One patient in the carvedilol arm and five on placebo had an EF below 50% at 6 months. There was one death in the carvedilol arm and four among controls (J. Am. Coll. Cardiol. 2006;48:2258–62).
Oxidative stress and mitochondrial dysfunction are believed to figure prominently in the pathophysiology of anthracycline-induced cardiomyopathy. The Turkish cardiologists pointed to carvedilol's antioxidant effects—considered the most potent of any β-blocker—as the most likely mechanism for the drug's ability to prevent cardiotoxicity. They selected a relatively low dosage because patients had normal baseline ventricular function and carvedilol's antioxidant properties are manifest even at lower doses.
Dr. Schroeder agreed that carvedilol's strong antioxidant effects make it the β-blocker of choice for prevention of CIC. He added, however, that the prolonged-release formulation probably makes more sense.
The other key clinical trial in the prevention of chemotherapy-induced cardiomyopathy was conducted by Dr. Daniela Cardinale and colleagues at the European Institute of Oncology in Milan.
Among 473 cancer patients with a normal baseline EF undergoing high-dose chemotherapy, they identified 24% as being at particularly high risk for CIC on the basis of a troponin I level greater than 0.07 ng/mL obtained within several days after completing any chemo cycle. The investigators randomized these 114 patients to 1 year of enalapril or to no enalapril beginning 1 month after the end of the final cycle of chemo. The ACE inhibitor was slowly titrated to 20 mg once daily.
The primary end point—a greater than absolute 10% drop in EF to a value below 50% at 1 year as assessed by blinded echocardiographers—occurred in 43% of controls and 0% of the ACE inhibitor recipients. In the control group there were 30 cases of the secondary combined end point of cardiac death, acute pulmonary edema, overt heart failure, or life-threatening arrhythmia, compared to just one in the enalapril group (Circulation 2006;114:2474–81).
The Italians surmised that the observed benefits involved a class effect and any ACE inhibitor would probably be effective. Dr. Schroeder agreed, adding that there are few data regarding the use of angiotensin II receptor blockers for this purpose.
In an earlier study Dr. Cardinale and colleagues showed that an increased troponin I level shortly after a cycle of high-dose chemotherapy was a strong predictor of cardiotoxicity, while patients with a normal troponin I didn't develop ventricular dysfunction. The highest risk was seen in patients whose troponin I was elevated early and again 1 month later (Circulation 2004;109:2749–54).
Thus, serial troponin I monitoring allows for a selective approach to the use of drugs aimed at preventing cardiotoxicity.
But Dr. Schroeder indicated he did not like the idea of waiting to treat until the troponin elevation indicated the disease process was underway. His preference is to prevent the troponin rise by starting prophylaxis before chemotherapy.
It's worthwhile to get an EF measurement in the middle and at the end of each cycle of chemotherapy and hold the chemo should the EF fall by more than 10% from baseline, he advised at the meeting, also sponsored by the American College of Cardiology.
Dr. Schroeder is on the speakers bureau for several pharmaceutical companies, including GlaxoSmithKline, which markets carvedilol.
Carvedilol's strong antioxidant effects make it the β-blocker of choice for prevention of CIC. DR. SCHROEDER