Calcium channel blockers "should not be used first-line therapy": inferior to other antihypertensive

Zosia Chustecka

August 30, 2000

Wed, 30 Aug 2000 16:58:59

Amsterdam, the Netherlands - Although calcium channel blockers (CCBs) are just as good as any other antihypertensive agents at lowering blood pressure, they are inferior when it comes to reducing the risk of two major cardiovascular complications of hypertension: myocardial infarction and heart failure. These findings, from a meta-analysis of 9 clinical trials involving a total of 27743 patients, are "epidemiologically, statistically and clinically solid," says Dr Curt Furberg (Professor, Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC). He adds that they show up a "major avoidable clinical problem that requires immediate attention."


"I'm not saying that calcium channel blockers should be taken off the market, but they should be used for hypertension only as drugs of last resort - in patients who do not respond to or cannot tolerate diuretics, beta-blockers, or ACE-inhibitors"


The meta-analysis, presented today at the 22nd Congress of the European Society of Cardiology in Amsterdam, found that patients talking CCB had a 27% increased risk of having an MI and a 26% increased risk of developing heart failure when compared with those taking other forms of antihypertensive therapy (diuretics, beta-blockers, ACE-inhibitors, and centrally-acting alpha-blockers). Furberg commented that extrapolation of these findings to the estimated 28 million patients currently taking CCBs worldwide suggests that there are up to 85,000 unnecessary cases of MIs or heart failure each year. These could be avoided by giving these patients another drug, he explained during a press conference following his presentation, and he suggested that all patients currently taking a CCB as first-line therapy for hypertension should be reassessed, and preferably treated instead with a low-dose diuretic. "I'm not saying that calcium channel blockers should be taken off the market, but they should be used for hypertension only as drugs of last resort - in patients who do not respond to or cannot tolerate diuretics, beta-blockers, or ACE-inhibitors."


The meta-analysis involved 9 clinical trials (ABCD, CASTEL, FACET, INSIGHT, MIDAS, NICS-EH, NORDIL, STOP2, VHAS) using a variety of CCBs - diltiazem, verapamil, and 6 different dihydropyridines: felodipine, amlodipine, isradipine, nifedipine, nisoldipine, and nicardipine. No differences among these drugs were found, but differences between the CCBs and the other antihypertensive drugs used were "remarkably consistent across the trials," Furberg said. The differences for both MI and heart failure were "highly, highly significant", he added.

Odds ratios for complications with CCB vs other antihypertensives


Odds Ratio

95% confidence interval

p value





Major CV events


Furberg emphasized the strengths of using a meta-analysis: the totality of the clinical trial evidence, including all trials and all major cardiovascular complications, the large numbers involved, which give adequate statistical power to show up a clinically meaningful 15% difference, and the internal consistency of the results across the trials. This contrasts with individual clinical trials, which lack statistical power, but also "downplay adverse trends and emphasize beneficial effects," he said.

Ongoing clinical trials with CCBs, such as ALLHAT and CONVINCE, may add additional information that could modify the results of the meta-analysis, but "are unlikely to reverse these conclusions," Furberg said. The findings join other "emerging evidence suggesting that how blood pressure is lowered is important." The ALLHAT study has already shown that doxazosin is inferior to a diuretic, and there is evidence for ACE-inhibitors being superior to other drugs in hypertensive diabetic patients. "It is becoming clear that lowering blood pressure per se is not enough."


"It is becoming clear that lowering blood pressure per se is not enough"


In an interview with heart wire , Furberg says that he feels vindicated by the new findings, having attracted controversy five years ago when he first voiced concerns over this class of drugs. At that time, however, the CCBs in use were short-acting agents, and the concerns were about safety. These have since been allayed by the newer long-acting preparations currently used, he said. "There is no evidence that these long-acting CCB cause harm, but we now have evidence that they are inferior."


Not only are they inferior, they are also vastly more expensive than many of the alternative therapies, Furberg said. Most diuretics and beta-blockers and some of the ACE-inhibitors are available as generics and are cheap; in the US, chlorthalidone costs around $60 a year. In contrast, the long-acting CCBs are still under patent protection and are up to 10-15 times more expensive - with costs for amlodipine (Norvasc) and nifedipine (Adalat, Procardia) ranging from $740 to 990 per year.


"Industry is driven by the bottom line, by profits . . . and to make money out of a good drug is fine, but to promote inferior drugs which are so much more expensive is unethical"


"Calcium channel blockers should not be prescribed as first line agents for hypertension," Furberg said, adding that marketing and promoting these drugs for such a use - in light of the findings of this meta-analysis - can now be considered unethical. Some of these agents are marketed very aggressively, and are phenomenally successful commercially - amlodipine (Pfizer's Norvasc) is the best-selling cardiovascular drug in the world. "This is because of marketing, and nothing else," says Furberg. "Industry is driven by the bottom line, by profits . . . and to make money out of a good drug is fine, but to promote inferior drugs which are so much more expensive is unethical." He also criticized the way in which many of these drugs have been developed and marketed, and believes that approval just on the basis of a surrogate end-point - a lowering of blood pressure - is wrong. The regulatory authorities should demand clinical end-points, showing a reduction in cardiovascular events.

"The aim of antihypertensive therapy is to reduce the health complications of hypertension, not just to lower the elevated blood pressure," stressed Furberg. "Growing evidence shows that it matters which drugs are used for blood pressure lowering." He urged all patients, on hearing this latest news, to consult their physicians and ask: are they being prescribed a proven therapy such as low dose diuretic? And if not, demand "why not?"

Mediapulse: Bad news for a best-selling class of therapy

New York, NY - The long, bitter debate over the use of calcium channel blockers (CCBs) for hypertension reached a higher level with a meta-analysis questioning their safety and effectiveness was released at the 22nd Annual European Society of Cardiology in Amsterdam, report national newspapers on August 29, 2000. The Wall Street Journal and New York Times report that the new study, a pooled analysis of nine randomized trials, shows that CCBs do not prevent MIs and congestive heart failure as well as other antihypertensives, as reported in heart wire .

"Calcium channel blockers are among the biggest-selling blood-pressure medicines in the world, and scientists have debated the class's relative risks and benefits compared with other popular blood-pressure drugs, such as ACE inhibitors," writes the Journal's Ron Winslow. He reports that the study found that patients who take CCBs have a 27% higher risk of MI and a 26% higher risk of heart failure than those taking other hypertension medications, including ACE inhibitors, beta blockers and diuretics. "The differences aren't related to blood pressure. The drugs all lower bloodpressure. But clinically we don't know which ones to use," says lead researcher Dr Curt D Furberg (Professor of Public Health, Wake Forest University School of Medicine).

"The report immediately drew criticism from Pfizer. Robert Scott, a vice president for medical issues at the New York-based drug company, said only 190 patients in the 9 studies evaluated in the analysis were on Norvasc. The company believes Norvasc acts differently than other drugs in the class. In addition, Dr Scott said some agents that were included in the report have a slightly higher risk of heart attack, but may be superior in reducing stroke," according to the Journal. "When you take it altogether there is really no difference," says Scott, who described the differences in risk as "small." "For a meta-analysis, 27% is not a large difference, particularly when total mortality is the same," Scott says.

The Journal notes that Furberg's group "caused an uproar" 5 years ago when they claimed that short-acting CCBs harmed patients. "Absent direct head-to-head trials, Dr Furberg said, 'too much is left to marketing forces. That's how drug companies want it,'" the paper reports. In the New York Times, Dr Furberg notes that CCBs are much more expensive than other antihypertensive drugs. "Wider use of more effective antihypertensive drugs could reduce the cost of health care in the UnitedStates by up to $5 billion a year, Dr Furberg said," writes Dr Lawrence Altman. Dr Furberg told the Times that CCBs should not be taken off the market, but that "doctors should be more cautious in prescribing them as first-line drug therapy for high blood pressure and to prevent its complications. Dr Furberg's team urged doctors to limit use of CCBs to patients who have not responded to or cannot tolerate other standard drugs. Low-dose diuretics should continue to be considered as the standard therapy for hypertension, and all new classes of drugs should be compared with diuretics, Dr Furberg's team said," writes Altman.

"Dr Furberg said that individually, the trials were too small to reach meaningful conclusions about the long-term effects of the drugs. While pooling the results isn't as statistically rigorous as a randomized study, he said it is the next best way to get comparative data," according to the Journal. The Times reports that Dr Robert Temple (Food and Drug Administration) said that his agency would "pay close attention to the new findings." "It hasn't been possible to do this before because there wasn't a great deal of comparative data," Temple says.

Two randomized, comparative CCB trials are underway, both newspapers note - the NIH-sponsored ALLHAT under Furberg's direction, with results due in 2002, and a Pfizer-sponsored trial comparing Norvasc plus an ACE inhibitor for patients who fail to reach a target blood pressure on Norvasc alone with a beta blocker plus a diuretic, with results expected in 2004. "I think they should wait until the large randomized trials" are completed, Scott says. "We have the trials that answer the questions they are posing." Temple told the Times that he agrees that "additional important information" would be available once these studies are published.

- Mark L Fuerst

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