Two-Drug Blood Pressure Therapy Reduces Heart Attacks

While doctors are urged to start with a diuretic-based strategy to control patients’ high blood pressure, an international blood pressure study shows a different single-pill drug combination is more effective at preventing heart-related events such as heart attacks and strokes. The findings challenge the way blood pressure is usually treated worldwide.

The randomized study led by a University of Michigan Health System researcher compared two drug combinations. The results, which appear in today’s New England Journal of Medicine, were so significant that the trial was stopped early.

Both single-pill combination drugs helped more than 75 percent of people who had high blood pressure and other cardiovascular risk factors get their blood pressure down. But even more important, patients in the study taking the combination that included a calcium channel blocker had 20 percent fewer heart-related events than the patients taking the other combination.

In all, 11,506 study participants took a single tablet that includes two medications. One group received a tablet containing benazepril, which is a type of drug called an ACE inhibitor, and amlodipine, which belongs to a class of drugs known as calcium channel blockers or CCBs. The other pill combined benazepril and hydrochloro-thiazide, a type of diuretic or “water pill.” The 20 percent reduction in cardiovascular events was observed with the ACE/CCB combination tablet.

Cardiovascular events were defined as cardiovascular deaths, heart attacks, strokes, hospitalizations for unstable angina and treatments to re-open blocked heart arteries.

Currently, national guidelines for the treatment of high blood pressure (also called hypertension) call for patients who need medication to start out on a single pill, usually a diuretic, or water pill, and to add other drugs only as needed to bring pressure down. But the new results may signal a need to change those guidelines.

The ACCOMPLISH study suggests physicians no longer give diuretics preferred status in treating patients.

“This robust study showed us that switching patients to a single-pill combination meant that twice as many patients got to their blood pressure goal, regardless of previous therapy,” says University of Michigan Health System’s Kenneth Jamerson, M.D., the leader of the study.

“The significant reduction in cardiovascular events we observed in patients will, I hope, show physicians that earlier use of a combination medication, especially with amlodipine, may be in the best interest of patients,” he says.

Jamerson is a professor of internal medicine at the University of Michigan Medical School and a member of the U-M Cardiovascular Center.

Results from the ACCOMPLISH trial show that just six months of treatment with either drug combination was enough to bring the blood pressure of 73 percent of
patients into an acceptable range – despite the fact that two-thirds were already taking some other medication before they entered the study. At the beginning of the trial, only 37 percent had blood pressure below 140/90.

However, by the end of the three-year trial blood pressure control rates were 80 percent, with average systolic blood pressure less than 130 mmHg. This represents exceptional blood pressure control when contrasted to the current control rate of about 30 percent in the United States.

Participants from five countries – the United States, Sweden, Norway, Denmark and Finland – were part of the trial, and all patients were at risk for cardiovascular events.

Many studies have already shown that reducing blood pressure can reduce the risk of stroke, heart attack, heart failure and other conditions, but many people have a very difficult time achieving blood pressure control.

As many as 73 million Americans have high blood pressure. But because high blood pressure doesn’t cause symptoms, most people who have it, don’t know it.

Over time, uncontrolled blood pressure affects the blood vessel walls, encouraging the growth of weak spots called aneurysms and the formation of narrowed and inflamed areas that can lead to clots that can break off and cause heart attacks and strokes.

Fortunately, once the condition is diagnosed, doctors have a broad range of medicines to choose from to try to get it under control, including many inexpensive generic medicines.

But studies have found that patients often have trouble taking the multiple medications they need. As a result, many companies have developed combination pills.

The study was funded by Novartis, which is among the companies that offer two-drug combination tablets for blood pressure treatment.
ACCOMPLISH stands for Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension.

Another “Smart” Cancer Drug Can Have Toxic Effects on the Heart

Description

Another FDA-approved targeted cancer drug, sunitinib (SutentTM, Pfizer), may be associated with cardiac toxicity, report researchers at Children’s Hospital Boston, Dana-Farber Cancer Institute, and Thomas Jefferson University. Sunitinib is one of several new “smart” cancer drugs called tyrosine kinase inhibitors that targets specific signaling molecules inside cancer cells that aid cancer spread.

Another FDA-approved targeted cancer drug, sunitinib (SutentTM, Pfizer), may be associated with cardiac toxicity, report researchers at Children’s Hospital Boston, Dana-Farber Cancer Institute (Boston), and Thomas Jefferson University (Philadelphia). Their collaborative study, led by Ming Hui Chen, MD, MMSc, a cardiologist at Children’s who specializes in the cardiac health of cancer patients, appears in the December 15 issue of The Lancet, accompanied by an editorial.

Sunitinib is one of several new “smart” cancer drugs called tyrosine kinase inhibitors that targets specific signaling molecules inside cancer cells that aid cancer spread. Another “targeted” cancer therapy, imatinib (GleevecTM, Novartis Pharmaceuticals), was reported last year in Nature Medicine to be associated with heart failure in patients with chronic myelogenous leukemia.

Sunitinib was originally thought to be relatively free of cardiac side effects. However, a new retrospective analysis, focused on cardiovascular events, revealed a risk for heart failure, myocardial infarction and hypertension in 75 adult patients with imatinib-resistant, gastrointestinal stromal tumor (GIST) receiving multiple cycles of sunitinib in a phase I/II trial at Dana-Farber.

Of the 75, six (8 percent) developed symptoms consistent with moderate-to-severe congestive heart failure, and two had heart attacks. In all, eight (11 percent) had some kind of cardiovascular event while receiving sunitinib at FDA-approved or lower doses. Patients with preexisting coronary artery disease were more likely to develop cardiac problems. Nineteen percent of the 36 patients receiving the FDA-approved dose had decreases in left ventricular ejection fraction, a measure of the heart’s pumping ability.

In addition, 47 percent (35 of 75) developed hypertension. “Hypertension is a common side effect with certain cancer drugs, but the degree of hypertension – both the percentage of affected patients and the magnitude of increase in systolic blood-pressure – was notable,” says Chen, who is also affiliated with Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School.

Two patient biopsies revealed abnormalities in the heart cells’ mitochondria (the structures responsible for energy production). Further studies, led by Maria Rupnick, MD, of the Children’s Hospital Boston Vascular Biology Program, and Thomas Force, MD, from the Center for Translational Medicine and Division of Cardiology at Jefferson, examined heart-muscle cells from mice who had received the equivalent of a human dosage of sunitinib alone, and found direct evidence of cardiotoxicity.

“Early identification of cardiac side effects is an important part of keeping patients on life-saving cancer therapy over the long-term,” says Chen. “In this study, the cardiac dysfunction and hypertension were usually medically manageable. Most importantly, patients were most often able to resume sunitinib therapy following temporary withholding of drug, addition of cardiac medications and/or dose adjustment.”

“This sunitinib study highlights potential concerns with agents that are ‘multi-targeted,’ meaning they inhibit multiple factors involved in cancer progression,” adds Force, who led the study of imatinib patients published in Nature Medicine last year. “Some of these factors may also play important roles in maintenance of proper heart function, and their inhibition by cancer drugs could have adverse effects on the heart.”

“The most important element of this new work is the close, creative collaboration between our medical oncology and cardiology teams,” says George Demetri, MD, a co-author on the paper and director of the Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School. “As our molecular targeting involves more pathways, we can inform one another’s fields and identify side effects early by working together across traditional disciplinary boundaries.”

“We are hopeful,” Chen concludes, “that this type of multidisciplinary approach, from the patient’s bedside to the basic cell biology laboratory, will lead to further pharmaceutical advances that will make these ‘smart’ cancer drugs even smarter.”

Children’s has a long history of researching the cardiovascular effects of cancer drugs. In children, such side effects are especially important to manage so they can survive the cancer in good health well into adulthood. In 1991, for example, Children’s cardiologists published the seminal finding that doxorubicin therapy for childhood leukemia can lead to clinically important heart disease.

Supporters of the sunitinib cardiovascular study included the Department of Cardiology, Children’s Hospital Boston; the Translational Research Fund for Cancer and Cardiology at Children’s Hospital Boston; a Long-Term Survivorship Grant from the Dana-Farber Cancer Institute; the National Heart, Lung and Blood Institute; the Finnish Heart Foundation; and the American Heart Association.

Children’s Hospital Boston is home to the world’s largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children’s research community. Founded as a 20-bed hospital for children, Children’s Hospital Boston today is a 377-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children’s also is the primary pediatric teaching affiliate of Harvard Medical School.(Newswise)