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A current evaluation of the safety of angiotensin receptor blockers and direct renin inhibitors.

Siragy HM - Vasc Health Risk Manag (2011)

Bottom Line: Less is known about the safety of the direct renin inhibitor aliskiren, which was approved as an antihypertensive in 2007.ARBs are generally well tolerated, with no known class-specific adverse events.An ongoing safety investigation by the FDA has not concluded that ARBs increase the risk of cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, and Hypertension Center, University of Virginia Health System, Charlottesville, VA 22908, USA. hms7a@virginia.edu

ABSTRACT
The safety of angiotensin II receptor blockers (ARBs) for the treatment of hypertension and cardiovascular and renal diseases has been well documented in numerous randomized clinical trials involving thousands of patients. However, recent concerns have surfaced about possible links between ARBs and increased risks of myocardial infarction and cancer. Less is known about the safety of the direct renin inhibitor aliskiren, which was approved as an antihypertensive in 2007. This article provides a detailed review of the safety of ARBs and aliskiren, with an emphasis on the risks of cancer and myocardial infarction associated with ARBs. Safety data were identified by searching PubMed and Food and Drug Administration (FDA) Web sites through April 2011. ARBs are generally well tolerated, with no known class-specific adverse events. The possibility of an increased risk of myocardial infarction associated with ARBs was suggested predominantly because the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial reported a statistically significant increase in the incidence of myocardial infarction with valsartan compared with amlodipine. However, no large-scale, randomized clinical trials published after the VALUE study have shown a statistically significant increase in the incidence of myocardial infarction associated with ARBs compared with placebo or non-ARBs. Meta-analyses examining the risk of cancer associated with ARBs have produced conflicting results, most likely due to the inherent limitations of analyzing heterogeneous data and a lack of published cancer data. An ongoing safety investigation by the FDA has not concluded that ARBs increase the risk of cancer. Pooled safety results from clinical trials indicate that aliskiren is well tolerated, with a safety profile similar to that of placebo. ARBs and aliskiren are well tolerated in patients with hypertension and certain cardiovascular and renal conditions; their benefits outweigh possible safety concerns.

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Incidence of cancer with A) ARB/ACE inhibitor combination vs ACE inhibitor alone, B) ARB alone vs ACE inhibitor alone, and C) ARB vs placebo/control with no ACE inhibitor.Reprinted from the Journal of Hypertension, volume 29, issue 4, the ARB trialists collaboration, ‘Effects of telmisartan, irbesartan, candesartan, and losartan on cancers in 15 trials enrolling 138 769 individuals’, pp 623–635, Copyright 2011, with permission from Wolters Kluwer Health.57Notes: In the LIFE study, atenolol was the control. *Included patients who were free of cancer at baseline.Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ACTIVE, Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; ARB, angiotensin receptor blocker; CHARM, Candesartan in Heart failure Assessment in Reduction of Mortality; CI, confidence interval; DIRECT, Diabetic Retinopathy Candesartan Trials; IDNT, Irbesartan in Diabetic Nephropathy Trial; I-PRESERVE, Irbesartan in Heart Failure With Preserved Systolic Function; LIFE, Losartan Intervention For Endpoint Reduction in Hypertension; ONTARGET, Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial; OR, odds ratio; PROFESS, The Prevention Regimen for Effectively Avoiding Second Strokes Trial; SCOPE, Study on Cognition and Prognosis in the Elderly; TRANSCEND, Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease; TROPHY, Trial of Prevention of Hypertension; Val-HeFT, Valsartan Heart Failure Trial; VALIANT, Valsartan in Acute Myocardial Infarction; VALUE, Valsartan Antihypertensive Long-Term Use Evaluation.
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f3-vhrm-7-297: Incidence of cancer with A) ARB/ACE inhibitor combination vs ACE inhibitor alone, B) ARB alone vs ACE inhibitor alone, and C) ARB vs placebo/control with no ACE inhibitor.Reprinted from the Journal of Hypertension, volume 29, issue 4, the ARB trialists collaboration, ‘Effects of telmisartan, irbesartan, candesartan, and losartan on cancers in 15 trials enrolling 138 769 individuals’, pp 623–635, Copyright 2011, with permission from Wolters Kluwer Health.57Notes: In the LIFE study, atenolol was the control. *Included patients who were free of cancer at baseline.Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ACTIVE, Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; ARB, angiotensin receptor blocker; CHARM, Candesartan in Heart failure Assessment in Reduction of Mortality; CI, confidence interval; DIRECT, Diabetic Retinopathy Candesartan Trials; IDNT, Irbesartan in Diabetic Nephropathy Trial; I-PRESERVE, Irbesartan in Heart Failure With Preserved Systolic Function; LIFE, Losartan Intervention For Endpoint Reduction in Hypertension; ONTARGET, Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial; OR, odds ratio; PROFESS, The Prevention Regimen for Effectively Avoiding Second Strokes Trial; SCOPE, Study on Cognition and Prognosis in the Elderly; TRANSCEND, Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease; TROPHY, Trial of Prevention of Hypertension; Val-HeFT, Valsartan Heart Failure Trial; VALIANT, Valsartan in Acute Myocardial Infarction; VALUE, Valsartan Antihypertensive Long-Term Use Evaluation.

Mentions: A third meta-analysis,57 conducted by the ARB Trialists Collaboration, evaluated the incidence of cancer in 15 long-term, randomized, controlled trials that involved 138,769 patients at high risk for cardiovascular disease who received ARBs (telmisartan, irbesartan, valsartan, candesartan, or losartan). In this analysis, the trials included were required to have an average follow-up time of at least 12 months. Similar to the Bangalore meta-analysis,56 no increased risk of cancer with ARBs was identified; the cancer incidence in the 15 trials was 6.16% (4549/73,808) in the ARB groups vs 6.31% (3856/61 106) in the control groups (odds ratio [OR]: 1.00; 95% CI: 0.95–1.04; P = 0.886). In addition, no increased cancer risk was observed when evaluating the individual ARBs, and no differences were observed in the incidences of lung, prostate, or breast cancers between ARBs and controls. This analysis also examined cancer risk of ARB/ACE inhibitor combinations vs ACE inhibitors alone, ARBs alone vs ACE inhibitors alone, and ARBs vs placebo/controls without ACE inhibitors. No increased risk of cancer was observed in any of these overall comparisons (Figure 3). A nominal increase in cancer risk was observed with the ARB/ACE inhibitor combination in one trial (ONTARGET) but a reduced cancer risk was observed with this combination in another (VALIANT). Thus, the authors concluded that the increased risk of cancer observed with the ARB/ACE inhibitor combination may be due to chance and that further study is needed to resolve this question.


A current evaluation of the safety of angiotensin receptor blockers and direct renin inhibitors.

Siragy HM - Vasc Health Risk Manag (2011)

Incidence of cancer with A) ARB/ACE inhibitor combination vs ACE inhibitor alone, B) ARB alone vs ACE inhibitor alone, and C) ARB vs placebo/control with no ACE inhibitor.Reprinted from the Journal of Hypertension, volume 29, issue 4, the ARB trialists collaboration, ‘Effects of telmisartan, irbesartan, candesartan, and losartan on cancers in 15 trials enrolling 138 769 individuals’, pp 623–635, Copyright 2011, with permission from Wolters Kluwer Health.57Notes: In the LIFE study, atenolol was the control. *Included patients who were free of cancer at baseline.Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ACTIVE, Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; ARB, angiotensin receptor blocker; CHARM, Candesartan in Heart failure Assessment in Reduction of Mortality; CI, confidence interval; DIRECT, Diabetic Retinopathy Candesartan Trials; IDNT, Irbesartan in Diabetic Nephropathy Trial; I-PRESERVE, Irbesartan in Heart Failure With Preserved Systolic Function; LIFE, Losartan Intervention For Endpoint Reduction in Hypertension; ONTARGET, Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial; OR, odds ratio; PROFESS, The Prevention Regimen for Effectively Avoiding Second Strokes Trial; SCOPE, Study on Cognition and Prognosis in the Elderly; TRANSCEND, Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease; TROPHY, Trial of Prevention of Hypertension; Val-HeFT, Valsartan Heart Failure Trial; VALIANT, Valsartan in Acute Myocardial Infarction; VALUE, Valsartan Antihypertensive Long-Term Use Evaluation.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3104607&req=5

f3-vhrm-7-297: Incidence of cancer with A) ARB/ACE inhibitor combination vs ACE inhibitor alone, B) ARB alone vs ACE inhibitor alone, and C) ARB vs placebo/control with no ACE inhibitor.Reprinted from the Journal of Hypertension, volume 29, issue 4, the ARB trialists collaboration, ‘Effects of telmisartan, irbesartan, candesartan, and losartan on cancers in 15 trials enrolling 138 769 individuals’, pp 623–635, Copyright 2011, with permission from Wolters Kluwer Health.57Notes: In the LIFE study, atenolol was the control. *Included patients who were free of cancer at baseline.Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ACTIVE, Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; ARB, angiotensin receptor blocker; CHARM, Candesartan in Heart failure Assessment in Reduction of Mortality; CI, confidence interval; DIRECT, Diabetic Retinopathy Candesartan Trials; IDNT, Irbesartan in Diabetic Nephropathy Trial; I-PRESERVE, Irbesartan in Heart Failure With Preserved Systolic Function; LIFE, Losartan Intervention For Endpoint Reduction in Hypertension; ONTARGET, Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial; OR, odds ratio; PROFESS, The Prevention Regimen for Effectively Avoiding Second Strokes Trial; SCOPE, Study on Cognition and Prognosis in the Elderly; TRANSCEND, Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease; TROPHY, Trial of Prevention of Hypertension; Val-HeFT, Valsartan Heart Failure Trial; VALIANT, Valsartan in Acute Myocardial Infarction; VALUE, Valsartan Antihypertensive Long-Term Use Evaluation.
Mentions: A third meta-analysis,57 conducted by the ARB Trialists Collaboration, evaluated the incidence of cancer in 15 long-term, randomized, controlled trials that involved 138,769 patients at high risk for cardiovascular disease who received ARBs (telmisartan, irbesartan, valsartan, candesartan, or losartan). In this analysis, the trials included were required to have an average follow-up time of at least 12 months. Similar to the Bangalore meta-analysis,56 no increased risk of cancer with ARBs was identified; the cancer incidence in the 15 trials was 6.16% (4549/73,808) in the ARB groups vs 6.31% (3856/61 106) in the control groups (odds ratio [OR]: 1.00; 95% CI: 0.95–1.04; P = 0.886). In addition, no increased cancer risk was observed when evaluating the individual ARBs, and no differences were observed in the incidences of lung, prostate, or breast cancers between ARBs and controls. This analysis also examined cancer risk of ARB/ACE inhibitor combinations vs ACE inhibitors alone, ARBs alone vs ACE inhibitors alone, and ARBs vs placebo/controls without ACE inhibitors. No increased risk of cancer was observed in any of these overall comparisons (Figure 3). A nominal increase in cancer risk was observed with the ARB/ACE inhibitor combination in one trial (ONTARGET) but a reduced cancer risk was observed with this combination in another (VALIANT). Thus, the authors concluded that the increased risk of cancer observed with the ARB/ACE inhibitor combination may be due to chance and that further study is needed to resolve this question.

Bottom Line: Less is known about the safety of the direct renin inhibitor aliskiren, which was approved as an antihypertensive in 2007.ARBs are generally well tolerated, with no known class-specific adverse events.An ongoing safety investigation by the FDA has not concluded that ARBs increase the risk of cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, and Hypertension Center, University of Virginia Health System, Charlottesville, VA 22908, USA. hms7a@virginia.edu

ABSTRACT
The safety of angiotensin II receptor blockers (ARBs) for the treatment of hypertension and cardiovascular and renal diseases has been well documented in numerous randomized clinical trials involving thousands of patients. However, recent concerns have surfaced about possible links between ARBs and increased risks of myocardial infarction and cancer. Less is known about the safety of the direct renin inhibitor aliskiren, which was approved as an antihypertensive in 2007. This article provides a detailed review of the safety of ARBs and aliskiren, with an emphasis on the risks of cancer and myocardial infarction associated with ARBs. Safety data were identified by searching PubMed and Food and Drug Administration (FDA) Web sites through April 2011. ARBs are generally well tolerated, with no known class-specific adverse events. The possibility of an increased risk of myocardial infarction associated with ARBs was suggested predominantly because the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial reported a statistically significant increase in the incidence of myocardial infarction with valsartan compared with amlodipine. However, no large-scale, randomized clinical trials published after the VALUE study have shown a statistically significant increase in the incidence of myocardial infarction associated with ARBs compared with placebo or non-ARBs. Meta-analyses examining the risk of cancer associated with ARBs have produced conflicting results, most likely due to the inherent limitations of analyzing heterogeneous data and a lack of published cancer data. An ongoing safety investigation by the FDA has not concluded that ARBs increase the risk of cancer. Pooled safety results from clinical trials indicate that aliskiren is well tolerated, with a safety profile similar to that of placebo. ARBs and aliskiren are well tolerated in patients with hypertension and certain cardiovascular and renal conditions; their benefits outweigh possible safety concerns.

Show MeSH
Related in: MedlinePlus