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8th February 2011
An analysis of randomised controlled trials (RCTs) found no evidence for a significantly increased risk of cancer and cancer related deaths with drugs commonly used for the treatment of hypertension including angiotensin II receptor antagonists (A2RAs). However, an increased risk of cancer with the combined use of an A2RA and an ACE inhibitor could not be ruled out.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Action
Health professionals should follow NICE guidelines for the management of hypertension. This study provides some reassurance that A2RAs and other antihypertensive agents (ACE inhibitors, diuretics, beta blockers, calcium channel blockers [CCBs]) are not associated with a significantly increased risk of cancer. A2RAs are an alternative to ACE inhibitors, where a renin-angiotensin system drug is indicated, but an ACE inhibitor is not tolerated (e.g. discontinued because of an intolerable ACE inhibitor-induced cough). In other circumstances, there is little robust evidence of a clinically significant benefit of combining an ACE inhibitor and an A2RA, except as a specialist second-line treatment for some patients with heart failure (see NICE CG 108). In addition, use of this combination increases the risk of side effects. Even though the increased risk of cancer seen in this study when an ACE inhibitor and an A2RA were used together was not significant in every analysis, the remaining uncertainty provides another good reason for limited use of this combination, and then only with careful monitoring.
What is the background to this?
In June 2010, a meta-analysis (MA) from Sipahi and colleagues of nine RCTs (n=94,570) was published, which provided a safety signal about a possible increased risk of cancer in people taking A2RAs (see MeReC Rapid Review No. 1525 for more details). The results of this MA led to safety reviews by both the European Medicines Agency and the FDA of the risk of cancer with A2RAs (reviews still ongoing). The study findings could not be treated as definitive due to inherent limitations of the data, e.g. the failure to include data from all relevant clinical studies, including the VALUE study. This more comprehensive analysis was carried out in response to these findings. This analysis considered a greater number of studies, using a variety of analytical techniques: direct comparison MA, indirect comparison (network) MA and trial sequential analysis.
What does this study claim?
From data identified from 70 RCTs (total n=324,168, mean follow-up 3.5 years), this study found no statistically significant increase in the incidence of cancer within individual antihypertensive agent classes (A2RAs, diuretics, ACE inhibitors, beta blockers, CCBs) compared with placebo by direct or indirect network (fixed-effect or random-effect model) MA or direct-comparison MA. However, a statistically significant increased risk of cancer with the combination of an ACE inhibitor and an A2RA compared with placebo was found in the fixed-effect (but not the random-effect) network analysis. No statistically significant increased risk of cancer death was found for any of the individual antihypertensive agent classes or the combination of an ACE inhibitor and an A2RA in any analysis versus placebo.
Trial sequential analysis suggested no evidence of a 5 to 10% relative risk (RR) increase of cancer and cancer related deaths within individual antihypertensive drug classes, but firm evidence for at least a 10% increased risk of cancer with use of an A2RA/ACE inhibitor combination.
How does this relate to other studies?
The carcinogenic potential of antihypertensive drugs has been debated for more than three decades, fuelled by conflicting data, mostly based on observational studies with inherent selection and ascertainment bias. The Sipahi MA of RCTs, using direct comparison analysis, found that A2RAs were associated with a statistically significant 8% increase in the risk of new cancer occurrence compared with controls (all trials), and an 11% increase in risk when analysis was limited to the three clinical trials where cancer was a pre-specified endpoint and cancer data was rigorously collected. These results were largely driven by studies with telmisartan▼, leading to speculation about whether the increased risk was with all A2RAs or with telmisartan alone. This more comprehensive analysis assessed the relationship of both A2RAs and other classes of antihypertensive agents with cancer; it included data from more than twice as many trials included in the previous meta-analysis.
So what?
This study, refutes the findings that telmisartan or A2RAs as a class (or other individual antihypertensive classes) are associated with a significantly increased risk of cancer. However, it did identify a possible harmful effect of A2RAs and ACE inhibitors when used in combination. It provides some reassurance that the use of A2RAs and other individual antihypertensive classes are not associated with a significantly increased risk of cancer, and if there is any increased relative risk, this is below 5%. On the other hand the suggestion that the A2RA and ACE inhibitor combination is associated with more than a 10% increased risk of cancer is of concern, and although not conclusively proven, is a good reason to take a cautious approach where its use is considered in the best interest of patients, for example, by specialists according to NICE guideline for the management of chronic heart failure. It should be noted that the increased risk with the A2RA/ACE inhibitor combination was largely driven by the ONTARGET study and further studies are required to conclusively prove the association.
The findings of this study are strengthened by the generally consistent associations obtained by the different analytical methods. However, there are limitations to the analysis which suggest caution when interpreting the findings. Although this study found no significantly increased cancer risk for individual antihypertensives, the mean duration of the studies was only 3.5 years, and it does not rule out association with cancers over the longer term, i.e. 3.5 years may not be sufficient for the identification of slowly developing cancers. The analysis did not consider dose of treatment and data was insufficient to take into account compliance issues or use a per-protocol strategy for the analysis. As several of the treatments are known to reduce cardiovascular morbidity and mortality, survival bias could also be a factor (i.e. cancer was more likely to be found in patients who received the antihypertensives because they lived longer because these drugs reduce cardiovascular mortality). Furthermore, because of the scarcity of data, the study could not rule out the possibility that antihypertensive drug classes are not associated with an increase in certain types of cancer, or that specific drugs within a class were associated with cancer.
Design
Traditional direct comparison MAs, multiple comparisons (network) MAs, and trial sequential analysis.
Patients
324,168 patients from 70 RCTs of antihypertensive drugs.
Intervention and comparison
Multiple comparisons of A2RAs, ACE inhibitors, beta blockers, CCB, or diuretics, and of the combination of A2RAs and ACE inhibitors with follow-up of at least 1 year. Primary outcomes were cancer and cancer-related deaths.
Outcomes and results
In the network MA (fixed-effect model) no significant differences were found in the risk of cancer with A2RAs (proportion with cancer 2.04%; odds ratio [OR] 1.01, 95% confidence interval [CI] 0.93 to 1.09), ACE inhibitor (2.03%; OR 1.00, 95%CI 0.92 to 1.09), beta blockers (1.97%; OR 0.97, 95%CI 0.88 to1.07), CCBs (2.11%; OR 1.05, 95%CI 0.96 to 1.13), diuretics (2.02%; OR 1.00, 95%CI 0.90 to 1.11), or other controls (1.95%; OR 0.97, 95%CI 0.74 to 1.24) versus placebo (2.02%). There was an increased risk with the combination of ACE inhibitor plus A2RA (2.30%; OR 1.14, 95%CI 1.02 to1.28); however, this risk was not apparent in the random-effects model (OR 1.15, 95%CI 0.92 to1.38). No differences were detected in cancer-related mortality for A2RAs (death rate 1.33%; OR 1.00, 95%CI 0.87 to 1.15), ACE inhibitor (1.25%; OR 0.95, 95%CI 0.81 to 1.10), beta blockers (1.23%; OR 0.93, 95%CI 0.80 to 1.08), CCBs (1.27%; OR 0.96, 95%CI 0.82 to 1.11), diuretics (1.30%; OR 0.98, 95%CI 0.84 to 1.13), other controls (1.43%; OR 1.08, 95%CI 0.78 to1.46), and ACE inhibitor plus A2RA (1.45%; OR 1.10, 0.90 to 1.32).
In direct comparison meta-analyses, when treatment with one class of drug was compared with any other control, no significant difference from controls were identified, except for an increased risk of cancer with ACE inhibitor plus A2RA (OR 1.14, 95%CI 1.04 to 1.24; P=0.004) and with CCBs (1.06; OR 1.01 to 1.12; P=0·02). Note that, in view of the multiple analyses, a P value of 0.02 is probably insufficient to demonstrate an effect with confidence. There was no significant difference in cancer-related mortality.
On the basis of trial sequential analysis, there was no evidence of a 5 to 10% RR increase of cancer and cancer-related deaths with any individual class of antihypertensive drugs studied. However, for the ACEi and A2RA combination, the cumulative Z curve crossed the trial sequential monitoring boundary, suggesting firm evidence for at least a 10% RR increase in cancer risk.
Sponsorship
No funding source.
More information on hypertension can be found on the Cardiovascular Disease – Hypertension section of NPC. More information on the use of ACE-inhibitors and A2RAs can be found in the Renin-Angiotensin Drugs (Rads) support materials.
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