Drugs are a necessary and ubiquitous part of medical treatment, but the potential for side effects may increase the risk of long-term cardiovascular problems. That would seem to be the primary message to be drawn from recent reports of adverse drug events over the past month that have put some popular pharmaceuticals in question. Some examples:

Three well-known patient advocacy groups have urged Merck & Co. (New York) and Pharmacia (Peapack, New Jersey) to test whether their top-selling arthritis drugs increase the risk of heart attack and stroke. The American Heart Association (Dallas, Texas), the National Stroke Association (Englewood, Colorado) and the Arthritis Foundation (Atlanta, Georgia) are urging immediate studies on Merck's Vioxx and Pharmacia's Celebrex products because of a recent report indicating that these medicines may cause blood clots that increase the risk of heart disease.

Vioxx and Celebrex, both just two years on the market, are designed to reduce ulcers and gastrointestinal problems and for the pharmas have blockbuster status – combined sales this year expected to be around $6 billion. They are the first members of a new class of arthritis treatments that work by selectively blocking the Cox-2 enzyme linked to inflammation.

Several weeks ago, the Journal of the American Medical Association published a study indicating that Cox-2 inhibitors might cause blood clots and trigger heart attack and stroke. And the research report called for a major new study to determine the safety of the drugs. Spokespersons for the National Stroke Association and Arthritis Foundation urged the firms to launch such a trial to better understand the increased risk of these drugs. In response, both Merck and Pharmacia have defended their products, pointing to clinical trials developed to support their clearances.

The German health ministry reported in early September that 616 people have died after taking Pfizer's (New York) anti-impotence drug Viagra, those figures coming from the Swedish-based Uppsala Monitoring Center. And the ministry said the German Institute for Pharmaceutical and Medical Products had recorded 77 deaths in the European Union and 30 in Germany. The ministry cautioned against drawing a cause-and-effect relationship, but suggested that the drug had been prescribed to those who had other existing health problems – such as heart disease or other circulatory illness – and so should have been contraindicated. Earlier this year, a study of Viagra following 5,600 users in England indicated that the drug did not increase the risk of heart attacks or heart disease. Despite the disclaimers issued by the health ministry, the report was followed by a drop of 3.5% in Pharmacia's share price.

A report issued by a group of Dutch researchers and published in the Archives of Internal Medicine last month has linked the use of birth control pills and menopause hormone supplements to the production of a urinary protein that, in turn, may be associated with kidney and cardiovascular problems. The research followed more than 4,300 Dutch women and those who used the estrogen-based pills were found to have double the risk of developing a condition called microalbuminaria, compared to those not taking the pills. The research did not follow the women long enough to determine if they developed either cardiovascular or kidney problems but said the findings support other research suggesting the connection between oral contraceptives or hormones and cardiovascular disease. Besides being an early sign of kidney disease, protein in the urine has been linked to increases in vascular problems and cardiovascular illness.

Not even antioxidant therapy escaped the bad press. Antioxidants have generally been offered as a panacea for many conditions, but a team of University of Washington (Seattle, Washington) researchers issued a report indicating that heart disease patients with low levels of HDL ("good") cholesterol, may do worse when antioxidants are added to simvastatin-niacin therapy. They found that antioxidants, including vitamin E and vitamin C, may reduce the effect of cholesterol-lowering statin drugs. Dr. Greg Brown and colleagues found that patients on simvastatin-niacin therapy who were given antioxidants had a lower increase in good cholesterol. According to the report, published in the August issue of Arteriosclerosis, Thrombosis, and Vascular Biology, a journal of the American Heart Association, the researchers randomly assigned 153 patients with coronary artery disease to one of four treatment groups: simvastatin-niacin; antioxidants only (vitamins E and C, beta-carotene and selenium); simvastatin-niacin plus antioxidants; or an inactive placebo. At one year, the placebo and antioxidant-only groups demonstrated minor changes in their blood fat, or lipid, profiles. The two groups that received simvastatin-niacin demonstrated similar significant reductions in plasma cholesterol, triglyceride and LDL cholesterol levels. However, the group that received simvastatin-niacin alone showed much greater increases in HDL cholesterol levels than the simvastatin-niacin plus antioxidants group. In addition, simvastatin-niacin, but not simvastatin-niacin plus antioxidants, produced beneficial changes in the quality of HDL particles.

Peripheral artery disease underdiagnosed

A new study indicates that physicians need to look closely not only at what is happening in the heart and around the heart but in the peripheral vasculature as well as an indicator of future heart problems. Published last month in the Journal of the American Medical Association, the study focuses on pereipheral artery disease (PAD) – a condition often found in the legs, where blood circulation can be poor – and that PAD needs to be more carefully assessed because of general systemic ramifications. Led by Alan Hirsch, MD, of the University of Minnesota (Minneapolis, Minnesota), the study examined 7,000 patients over 50 years of age, some of whom had a history of smoking or diabetes. It found that 29% suffered from peripheral arterial disease (PAD) and that half of those diagnosed with PAD in the study had not been diagnosed before. The condition was found to be just as common among women as men, and that it impacted all races about equally.

Arterial disease occurs when essential blood vessels are constricted by a buildup of fat deposits. Often painful, it was associated with potentially deadly heart attacks, strokes and blood clots, Hirsch wrote in the study. Despite the availability of a detection test that measures blood pressure in arteries in extremities and an array of drugs that can ease PAD, many people suffering from it go undiagnosed and untreated.

Exercise BP seen as key measure

Blood pressure readings are most often taken while we are sitting and at rest. But a study presented last month at the American Association of Cardiovascular and Pulmonary Rehabilitation meeting in Minneapolis, Minnesota said that changes in blood pressure during exercise may be a better indicator of underlying heart dysfunction. Researchers followed 35 adults with mild, untreated high blood pressure, measuring their blood pressure at rest and then during a later treadmill test. They also measured how well each person's blood vessels functioned. In particular, the researchers measured the difference between systolic and diastolic pressure, or pulse pressure, with a larger than normal difference between the two numbers indicating artery stiffness and increased risk of cardiovascular disease.

The research team, led by Kerry Stewart, MD, of Johns Hopkins University School of Medicine (Baltimore, Maryland), found that those with high pulse pressures during exercise were most likely to have weaker function of the endothelial cells lining their blood vessels. Those cells need to be able to contract and relax appropriately to allow for blood flow and poor functioning of these vessels indicates poor cardiovascular health, Stewart said. The inability to accommodate blood flow forces the heart to work harder, raising blood pressure and possibly leading to heart failure or stroke, he said.