Two decades ago a large randomised blood pressure trial called ALLHAT reported that a cheap diuretic ( chlorthalidone) was as good, if not superior,to other drugs such as a calcium channel blocker (CCB) or an an angiotensin converting enzyme inhibitor (ACEI). A diuretic was found to be better than a CCB in preventing congestive heart failurE, and superior to lisinopril (ACEI) in lowering BP and in preventing stroke, heart failure, and angina.
The researchers suggested that thiazide-type diuretics should be considered first line for drug therapy in patients with hypertension, Crucially there were no commercial sponsors involved in this trial.
Hypertension mandates lowering blood pressure to a reasonable extent in order to derive maximum clinical advantage. Substantial reduction in cardiovascular events are observed with optimal blood pressure therapy, with significant reduction in deaths, myocardial infarction, stroke, heart failure and unstable angina requiring intervention. The ALLHAT trial emphasised that there is little to choose between different medicines.
Another class of medicine termed angiotensin receptor blocker (ARB) came into existence soon after publication of the ALLHAT trial . An ARB is used to treat high blood pressure ,congestive heart failure, or diabetes kidney disease.
Over the years ARB’s became popular with most clinicians across the world. Recently, however, regulatory agencies have become concerned about a carcinogenic potential of this class of drugs. ARB’s get contaminated by nitrosamines and azido compounds that are carcinogenic. Randomised trials with ARB’s have shown increased risk of cancers , including lung cancer.
In 2011 more than 200 million patients were on ARB’s. There must be more now. In 2018 regulatory agencies recognised that nitrosodimetylamine, nitrosodiethylamine, and azido compunds were contaminating ARB’s, and demanded recalls of certain lots.
Recently a meta-analysis including 15 randomised trials has suggested a highly significant correlation between cumulative intake of an ARB and risk of all cancers (PLOS; 2nd March 2022). Increased risk was also observed with lung cancer. The meta-analysis included 74,000 patients exposed to high dose of an ARB compared to 62,000 serving as a comparator group. There was a significantly increased risk in all cancers when an ARB was used for more than 3 years, and significant increase in lung cancer when the drug was employed for 2.5 years only.
As opposed to above when an ARB was used at a low dose, and for a shorter duration of time, there was no signal of increased risk in cancer. This meta-analysis was done at a trial level, and therefore effects of age and smoking status could not be examined. Irbesartan, losartan, candesartan and valsartan were found to be associated with raised cancer risk.
In 2015 however a patient level meta-analysis does by an FDA researcher clearly showed significant increased risk of lung cancer by 24%, and worryingly survival of only 34% of these patients at one year. Predictably, FDA lawyers redacted enough data to prevent publication of this research. Moreover FDA refused to review the data or add a warning in the product package.
Two big trials with telmisartan ( ONTARGET and TRANSCEND) were published in 2008.The TRANSCEND trial stated “a higher rate of malignancies was observed in patients treated with telmisartan than in those treated with placebo” and “so far, there is no evidence that ARBs are associated with a higher risk of malignancies, chance findings due to multiple testing cannot be excluded”. Similarly, in the ONTARGET trial telmisartan was associated with increased risk of can her by 12-14%.
Importantly, ACEinhibitors had no effect on incident cancer in long-term randomized controlled trials including more than 60.000 patients (RR 1.01 [95% CI 0.95 to 1.07]) .
Also, given the numbers needed to harm of 120 for one excess cancer ,and 464 for one excess lung cancer, it can be projected that if 200 million patients are exposed to daily high doses for 4.7 years (or equivalent), approximately 1.7 million excess cancers (and 430,000 lung cancers in 4.6 years) could be potentially caused by this class of drugs.
Also, there is actual evidence that ARBs may be inferior to many other classes of antihypertensives for prevention of mortality and cardiac morbidity. For example, while ACE inhibitors reduce total mortality and risk of myocardial infarction in hypertensives, ARBs do not reduce the risk. ARBs have not been shown to reduce myocardial infarction, even in placebo controlled trials.
It is imperative that more research is conducted regarding the association of increased cancer risk with ARB’s because of their wide use in patients with heart failure and hypertension. A temporary pause would not be difficult because as mentioned earlier there are multiple drugs that are equally if not more effective.
References
1) Risk of cancer with angiotensin-receptor blockers increases with increasing cumulative exposure: Meta-regression analysis of randomized trials. PLOS 2nd March 2021.
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2) Burton TM. Dispute Flares Inside FDA Over Safety of Popular Blood-Pressure Drugs. 2013. https:// www.wsj.com/articles/SB10001424127887324682204578515172395384146 (last accessed on Janu- ary 5, 2022).
3) Center for Drug Evaluation and Research Application Number: 206316Orig1Orig2s000 MEDICAL REVIEW(S). 2015. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/ 206316Orig1Orig2s000MedR.pdf (last accessed on January 5, 2022).
4)Nissen SE. Angiotensin-receptor blockers and cancer: urgent regulatory review needed. Lancet Oncol 2010; 11:605–606. https://doi.org/10.1016/S1470-2045(10)70142-X PMID: 20542469
5) Strauss MH, Hall AS. Angiotensin Receptor Blockers Do Not Reduce Risk of Myocardial Infarction, Car- diovascular Death, or Total Mortality: Further Evidence for the ARB-MI Paradox. Circulation 2017; 135:2088–2090. https://doi.org/10.1161/CIRCULATIONAHA.117.026112 PMID: 28559493
6)Singh A, Bangalore S. Do angiotensin receptor blockers prevent myocardial infarctions as well as other initial therapies? Curr Opin Cardiol 2012; 27:381–385. https://doi.org/10.1097/HCO. 0b013e328353bc68 PMID: 22525329
7) Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or calcium channel blocker vs diuretic.The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) JAMA. 2002;288:2981-2997
8) Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547–1559. https://doi.org/10.1056/ NEJMoa0801317 PMID: 18378520
9)Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 2008; 372:1174–1183. https://doi.org/10.1016/ S0140-6736(08)61242-8 PMID: 18757085
10) Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008; 359:1225–1237. https://doi.org/10.1056/ NEJMoa0804593 PMID: 18753639