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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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ARBs and cancer risk A) and cancer-related death B), stratified by ARB type (telmisartan or other).Reprinted from The Lancet Oncology, volume 12, issue 1, Bangalore et al, ‘Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324 168 participants from randomised trials’, pp 65–82, Copyright 2011, with permission from Elsevier.56Note: The size of the data marker represents the weight of each trial. CHARM-added and Val-HeFT trials were excluded because they were regarded as ACEi and ARB combination trials.Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ALPINE, Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation; ARBs, angiotensin receptor blockers; CHARM, Candesartan in Heart failure Assessment in Reduction of Mortality; CI, confidence interval; E-COST, Efficacy of Candesartan on Outcome in Saitama Trial; GISSI-AF, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico–Atrial Fibrillation; HIJ-CREATE, Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease; IDNT, Irbesartan Diabetic Nephropathy Trial; I-PRESERVE, Irbesartan in Heart Failure With Preserved Systolic Function; IRMA-2, Irbesartan in Microalbuminuria, Type 2 Diabetic Nephropathy Trial; LIFE, Losartan Intervention For Endpoint Reduction in Hypertension; OPTIMAL, Optimal Trial In Myocardial Infarction With the Angiotensin Receptor Blocker Losartan; 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; RENAAL, Reduction of Endpoints in Non-insulin-dependent Diabetes Mellitus With Angiotensin II Antagonist Losartan; ROAD, Renoprotection of Optimal Antiproteinuric Doses; TRANSCEND, Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease; TROPHY, Trial of Prevention of Hypertension; VALIANT, Valsartan in Acute Myocardial Infarction; VALUE, Valsartan Antihypertensive Long-Term Use Evaluation.
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f2-vhrm-7-297: ARBs and cancer risk A) and cancer-related death B), stratified by ARB type (telmisartan or other).Reprinted from The Lancet Oncology, volume 12, issue 1, Bangalore et al, ‘Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324 168 participants from randomised trials’, pp 65–82, Copyright 2011, with permission from Elsevier.56Note: The size of the data marker represents the weight of each trial. CHARM-added and Val-HeFT trials were excluded because they were regarded as ACEi and ARB combination trials.Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ALPINE, Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation; ARBs, angiotensin receptor blockers; CHARM, Candesartan in Heart failure Assessment in Reduction of Mortality; CI, confidence interval; E-COST, Efficacy of Candesartan on Outcome in Saitama Trial; GISSI-AF, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico–Atrial Fibrillation; HIJ-CREATE, Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease; IDNT, Irbesartan Diabetic Nephropathy Trial; I-PRESERVE, Irbesartan in Heart Failure With Preserved Systolic Function; IRMA-2, Irbesartan in Microalbuminuria, Type 2 Diabetic Nephropathy Trial; LIFE, Losartan Intervention For Endpoint Reduction in Hypertension; OPTIMAL, Optimal Trial In Myocardial Infarction With the Angiotensin Receptor Blocker Losartan; 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; RENAAL, Reduction of Endpoints in Non-insulin-dependent Diabetes Mellitus With Angiotensin II Antagonist Losartan; ROAD, Renoprotection of Optimal Antiproteinuric Doses; TRANSCEND, Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease; TROPHY, Trial of Prevention of Hypertension; VALIANT, Valsartan in Acute Myocardial Infarction; VALUE, Valsartan Antihypertensive Long-Term Use Evaluation.

Mentions: Subsequently, a second meta-analysis56 was performed to assess whether there is an increased risk of cancer associated with antihypertensive therapy. Results of this analysis56 refuted the results of the Sipahi study.13 In their meta-analysis, Bangalore and colleagues identified 70 randomized clinical trials of antihypertensive agents (ARBs, ACE inhibitors, calcium-channel blockers, and diuretics) involving 324,168 patients and found no increased risk of cancer associated with ARBs compared with placebo or other antihypertensive controls using random-effects and fixed-effect models (Table 5).56 However, in a fixed-effect model, the combination of ARBs with ACE inhibitors was associated with an increased cancer risk compared with placebo and compared with ARBs (Table 5). When the results of individual trials of ARBs were evaluated for cancer risk and cancer-related death, ARBs did not differ significantly vs comparators (Figure 2). In addition, results did not differ for telmisartan compared with other ARBs.


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

Siragy HM - Vasc Health Risk Manag (2011)

ARBs and cancer risk A) and cancer-related death B), stratified by ARB type (telmisartan or other).Reprinted from The Lancet Oncology, volume 12, issue 1, Bangalore et al, ‘Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324 168 participants from randomised trials’, pp 65–82, Copyright 2011, with permission from Elsevier.56Note: The size of the data marker represents the weight of each trial. CHARM-added and Val-HeFT trials were excluded because they were regarded as ACEi and ARB combination trials.Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ALPINE, Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation; ARBs, angiotensin receptor blockers; CHARM, Candesartan in Heart failure Assessment in Reduction of Mortality; CI, confidence interval; E-COST, Efficacy of Candesartan on Outcome in Saitama Trial; GISSI-AF, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico–Atrial Fibrillation; HIJ-CREATE, Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease; IDNT, Irbesartan Diabetic Nephropathy Trial; I-PRESERVE, Irbesartan in Heart Failure With Preserved Systolic Function; IRMA-2, Irbesartan in Microalbuminuria, Type 2 Diabetic Nephropathy Trial; LIFE, Losartan Intervention For Endpoint Reduction in Hypertension; OPTIMAL, Optimal Trial In Myocardial Infarction With the Angiotensin Receptor Blocker Losartan; 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; RENAAL, Reduction of Endpoints in Non-insulin-dependent Diabetes Mellitus With Angiotensin II Antagonist Losartan; ROAD, Renoprotection of Optimal Antiproteinuric Doses; TRANSCEND, Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease; TROPHY, Trial of Prevention of Hypertension; VALIANT, Valsartan in Acute Myocardial Infarction; VALUE, Valsartan Antihypertensive Long-Term Use Evaluation.
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Related In: Results  -  Collection

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f2-vhrm-7-297: ARBs and cancer risk A) and cancer-related death B), stratified by ARB type (telmisartan or other).Reprinted from The Lancet Oncology, volume 12, issue 1, Bangalore et al, ‘Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324 168 participants from randomised trials’, pp 65–82, Copyright 2011, with permission from Elsevier.56Note: The size of the data marker represents the weight of each trial. CHARM-added and Val-HeFT trials were excluded because they were regarded as ACEi and ARB combination trials.Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ALPINE, Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation; ARBs, angiotensin receptor blockers; CHARM, Candesartan in Heart failure Assessment in Reduction of Mortality; CI, confidence interval; E-COST, Efficacy of Candesartan on Outcome in Saitama Trial; GISSI-AF, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico–Atrial Fibrillation; HIJ-CREATE, Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease; IDNT, Irbesartan Diabetic Nephropathy Trial; I-PRESERVE, Irbesartan in Heart Failure With Preserved Systolic Function; IRMA-2, Irbesartan in Microalbuminuria, Type 2 Diabetic Nephropathy Trial; LIFE, Losartan Intervention For Endpoint Reduction in Hypertension; OPTIMAL, Optimal Trial In Myocardial Infarction With the Angiotensin Receptor Blocker Losartan; 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; RENAAL, Reduction of Endpoints in Non-insulin-dependent Diabetes Mellitus With Angiotensin II Antagonist Losartan; ROAD, Renoprotection of Optimal Antiproteinuric Doses; TRANSCEND, Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease; TROPHY, Trial of Prevention of Hypertension; VALIANT, Valsartan in Acute Myocardial Infarction; VALUE, Valsartan Antihypertensive Long-Term Use Evaluation.
Mentions: Subsequently, a second meta-analysis56 was performed to assess whether there is an increased risk of cancer associated with antihypertensive therapy. Results of this analysis56 refuted the results of the Sipahi study.13 In their meta-analysis, Bangalore and colleagues identified 70 randomized clinical trials of antihypertensive agents (ARBs, ACE inhibitors, calcium-channel blockers, and diuretics) involving 324,168 patients and found no increased risk of cancer associated with ARBs compared with placebo or other antihypertensive controls using random-effects and fixed-effect models (Table 5).56 However, in a fixed-effect model, the combination of ARBs with ACE inhibitors was associated with an increased cancer risk compared with placebo and compared with ARBs (Table 5). When the results of individual trials of ARBs were evaluated for cancer risk and cancer-related death, ARBs did not differ significantly vs comparators (Figure 2). In addition, results did not differ for telmisartan compared with other ARBs.

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