Recently the media has reported that a class of blood pressure medicine known as angiotensin-receptor blocker (ARB) used by tens of millions of patients can cause a significant increase in cancer especially lung cancer. This was the conclusion drawn from a study published online recently by
Sipahi et al in the medical journal Lancet Oncology.A cascade of hormonal reactions mainly referred to as the renin-angiotensin-aldosterone (RAA) hormonal system is central in maintaining blood pressure. The first step in the chain is the production of renin in the kidneys when the kidneys detect lower blood pressure. Renin then stimulates the formation of a protein called Angiotensin I, which is then converted to angiotensin II by the angiotensin converting enzyme (ACE) in the lungs. Angiotensin II is the most powerful constrictor of blood vessels known and this constriction leads to elevated blood pressure. Angiotensin II also causes the secretion of the hormone aldosterone which further causes an additional blood pressure rise. Any drug that prevents the production of Angiotensin II via the RAA system therefore is useful in reducing blood pressure. The two classes of drugs that have the most substantial effects on the RAA system are the angiotensin receptor blockers (ARB) drugs and the angiotensin converting enzyme inhibitors (ACE inhibitors) and are widely used for the treatment of hypertension, heart failure and diabetes-related kidney damage. The mechanisms of action of both these drugs are different although producing the same end result: reduction in blood pressure or is antihypertensive. For instance, ACE inhibitors lower blood pressure not only by blocking the production of Angiotensin II, but by increasing the amounts of powerful chemicals, including nitric oxide, that widen the arteries.
Ever since the use of reserpine, a drug used for hypertension but no longer used, has been associated with an increased risk of breast cancer more than 50 years ago, the question of antihypertensive drugs and cancer has not come to rest. Beta-blockers have been associated with lung cancer, thiazide diuretics with renal cell carcinoma and colon cancer and calcium blockers with cancer in general. In most instances, the risk is small and not supported by biochemical experimental or epidemiological data. The relationship between diuretic therapy and renal cell carcinoma is supported by a variety of clinical biochemical and experimental data and remains of concern, particularly in women.
An association between the ACE inhibitors and cancer was first indicated when the results of the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) study were published in 2003. The results of the CHARM trial indicated that patients treated with candesartan had a significant increase in the risk for fatal cancers compared with control patients but that the investigators concluded this finding was likely due to chance. Since then, several other studies, including LIVE, ONTARGET and TRANSCEND noted an excess in malignancies in patients assigned the ARBs compared with placebo.
For that reason, Sipahi et al conducted the meta-analysis to determine if ARBs had an effect on new cancer diagnoses. Data were taken from all available scientific and public randomized trials in which patients were treated with an angiotensin-receptor blocker to treat hypertension, heart failure and diabetes-related kidney damage. The five trials with new cancer data were ONTARGET, PROFESS, LIFE, TRANSCEND, and CHARM-Overall. In addition, data were available for cancer deaths in LIFE, TRANSCEND, VALIANT, and Val-HeFT. In 85.7% of the trials examined, Telmisartan which is also marketed as Micardis, among other names was used. Telmisartan has been commercially available to treat hypertension since its approval in 1998. It is also approved for use in the reduction of the risk of myocardial infarction, stroke, or death from cardiovascular diseases (CVD) in patients 55 years of age or older who were at high risk of developing major CV events and who are unable to take ACE inhibitors. Hence, it is really the effect of telmisartan on new cancer that is being accessed in this meta-analysis.
The analysis followed about 61,590 patients: researchers found a rise of 11 percent in cancer overall and 25 percent in lung cancer among patients who took ARB drugs. Overall those patients on trial who were randomly assigned an ARB had an increased risk for new cancer diagnosis compared with those patients assigned placebo (7.2% vs. 6%). Among the solid-organ cancers examined, only an increased risk for lung cancer was identified compared with control groups (0.9% vs. 0.7%). That translates into the modest but significant effect of one additional case of cancer for every 105 patients who take the drugs for four years, which does not seem a high risk but is similar to that seen with passive smoking. Nevertheless, this is the first time such an association has been made and even if the risk for the individual patient is not huge, the clinical significance of this potential excess cancer risk is unknown.
Given the millions of patients on these drugs, this is an important number because it gives an idea of potentially how many excess cancers could be caused by these medications. The finding of a 1.2% increase in absolute risk for cancer over an average of 4 years needs to be interpreted in view of the estimated 41% lifetime cancer risk. In the background information for this meta-analysis, the researchers said, to date, there have been no significant safety concerns associated with the use of ARBs. "However, clinical trials of ARBs have mainly assessed their effects on cardiovascular and renal endpoints and have usually not reported incidence of cancers," the researchers wrote. Angiotensin-receptor blockers can be replaced with other blood pressure medications, the researchers said, but they warned patients not to do anything before consulting with a physician as these drugs have beneficial effects for the control of blood pressure and heart failure.
Officials with Boehringer Ingelheim, makers of Telmisartan, disputed the findings in a statement, saying that the company's "comprehensive internal safety data analysis of primary data contradicts the conclusions about an increased risk of potential malignancies." They also concluded that the finding of a modestly increased risk of new cancer diagnosis in the meta-analysis is "mainly based on the combination arm of telmisartan and ramipril [Altace, King Pharmaceuticals], an ACE inhibitor, in ONTARGET and not on the trial arms of each compound separately," it asserts, noting that the product labelling for telmisartan does not recommend combining it with ACE inhibitors.
In most studies and meta-analyses, the risk of cancer with the RAA system blockers was either equal or lower than with their comparator (including placebo). Thus, the present study showing a modestly increased risk of new cancer diagnosis with ARBs is unexpected and certainly warrants scrutiny and further investigation. While the meta-analysis has its strengths-particularly its size, the thoroughness of the literature search, and the application of appropriate filters to exclude potentially unreliable data, "there are also important weaknesses, which the investigators acknowledge-including the post-hoc nature of this investigation where only certain drugs within the ARB class are examined and that the trials examined were not designed to explore cancer endpoints.
In an editorial accompanying this meta-analysis, Steven E. Nissen, said although the researchers are "appropriately cautious" about drawing conclusions from the analysis as it remains unknown whether other ARBs-irbesartan (Avapro, Bristol-Myers Squibb/Sanofi-Aventis), valsartan (Diovan, Novartis), olmesartan (Benicar, Daiichi Sankyo), and eprosartan (Teveten, Abbott)-are linked to a higher risk of new cancer incidence, it was still "disturbing and proactive". Further investigation is needed to conclusively define any cancer risk associated with these drugs. Also, the mechanism for the possible increase in new cancer occurrences associated with ARBs is uncertain, according the authors. There is little, if any, biological plausibility that a drug exposure of a few years only would increase the risk of new cancer diagnosis. Cigarette smoking, which is one of the most powerful risk factors for lung cancer, will require 10 years or longer of exposure to significantly increased risk of lung cancer. Thus, it's exceedingly unlikely that the short-term drug exposure as happens in clinical trials ARBs would have a clinically meaningful effect. Nevertheless, regulators must review the possible association between ARB use and cancer, and promptly report their findings. In the meanwhile, ARBs which are often over prescribed anyway, should be reserved for patients with intolerance to ACE inhibitors.
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