New Hypothesis Explains Why Drugs Increase Risk of Heart Attacks and Strokes

New research shows that medications that have raised safety concerns over heart attack and stroke risks may not have gotten approval from the Food and Drug Administration (FDA) if the cardiovascular effects of fluid retention had been better understood. Fluid retention may explain the increased risk of heart attacks and strokes of medications such as Vioxx (rofecoxib), Bextra (valdecoxib), and Avandia (rosiglitazone).

“This paper demonstrates that fluid retention is unhealthy because it increases the likelihood that blood will flow in a turbulent manner regardless of whether or not blood pressure is raised. Therefore, drugs that cause the body to retain fluid are dangerous for the cardiovascular system,” the study’s author, Robert P. Blankfield, MD, MS, clinical professor of family medicine at Case Western Reserve University School of Medicine, said in a press release.

“If the FDA had been aware of the increased cardiovascular risk that arises from drugs that cause fluid retention, Vioxx, Bextra, and Avandia might never have been approved. These findings might spur the FDA to alter some of its current policies,” he added.

The research, published in Clinical Hemorheology and Microcirculation, calculated the effects of fluid retention upon the velocity of blood flow and the turbulence of flowing blood. These calculations demonstrate that fluid retention increases the risk of heart attacks and strokes. Since numerous medications cause fluid retention, the paper’s findings have implications to ensure drugs on the market are safe.

The pain medications Vioxx and Bextra, and the anti-diabetic medication Avandia, cause fluid retention. Vioxx and Bextra, known as cyclo-oxygenase-2 (COX-2) inhibitors, were withdrawn from the market because of safety concerns over heart attacks and strokes, and Avandia has been suspected in some reports of increasing the risk of heart attacks.

Blankfield, who is also a member of the Department of Family Medicine at University Hospitals Case Medical Center, used several basic cardiovascular and hydraulic equations to demonstrate that fluid retention is detrimental for the cardiovascular system. Fluid retention increases the likelihood that blood will flow in a turbulent manner.

Turbulent blood flow accelerates atherosclerosis, thereby increasing the risk of heart attacks and strokes. Many medications cause fluid retention, which raises blood pressure in some, but not all, individuals. Physicians worry about fluid retention if it does raise blood pressure, but are unconcerned when blood pressure is unaffected.

“The calculations in this paper might also help pharmaceutical manufacturers screen drugs for their cardiovascular risk at an early stage in the drug development process,” Blankfield said. The cardiovascular safety problems with Avandia have prompted the FDA to require verification of cardiovascular safety for new anti-diabetic medications.

It is Dr. Blankfield’s opinion that this response by the FDA does not go far enough. “Based upon the calculations in the manuscript, the FDA ought to require verification of cardiovascular safety for all medications, old as well as new, that cause fluid retention.”

Several older anti-diabetic medications cause fluid retention, including insulin and sulfonylureas (glyburide, glipizide, glimerperide). The paper suggests it would make more sense to scrutinize these older anti-diabetic medications for cardiovascular safety than to scrutinize newer anti-diabetic medications, such as saxagliptin, that do not cause fluid retention.

If Blankfield’s mathematical analysis accurately reflects the workings of the cardiovascular system:

• pharmaceutical manufacturers may be able to identify the cardiovascular risk of drugs by utilizing basic principles of hemodynamics and hydraulics;

• the FDA may be able to assure the cardiovascular safety of all drugs by mandating that pharmaceutical manufacturers obtain detailed data on those drugs that cause fluid retention but do not lower blood pressure; and

• for drugs that have beneficial effects but also cause fluid retention, it may be possible for patients to safely use these drugs if they simultaneously use a water pill.