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PRIORITY PAPER EVALUATION
Comparative effectiveness of renin–angiotensin system inhibitors in hypertension C Michael White Evaluation of: Powers BJ, Coeytaux RR, Dolor RJ et al. Updated report on comparative effectiveness of ACE inhibitors, ARBs, and direct renin inhibitors for patients with essential hypertension: much more data, little new information. J. Gen. Intern. Med. doi:10.1007/s11606-011-1938-8 (2012) (Epub ahead of print). Hypertension is a chronic problem in the USA and there are three main ways to block the renin–angiotensin system: direct renin inhibitors, angiotensinconverting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). This article is a summary of a direct comparative effectiveness review of direct comparative trials in patients with hypertension. In patients with hypertension, ACEIs and ARBs provide similar blood pressure effects and no differences were seen in final health outcomes. ARBs have less ACE-induced cough and fewer withdrawals due to adverse events. Direct renin inhibitors versus ACE inhibitors or ARBs have not been extensively studied and their role is less clear.
University of Connecticut School of Pharmacy, 80 Seymour Street, Hartford, CT 06102-5037, USA Tel.: +1 860 545 2469 Fax: +1 860 545 2277 [email protected]
Keywords: angiotensin-converting enzyme inhibitor n angiotensin receptor blocker n direct comparison n hypertension n renin inhibitor
Approximately 75 million Americans have hypertension, which can be treated with a myriad of medications including diuretics, b‑blockers, calcium-channel blockers and renin–angiotensin (AT) system inhibitors [1] . Renin–AT system inhibitors include direct renin inhibitors (DRIs), AT-converting enzyme inhibitors (ACEIs) and AT receptor blockers (ARBs). Renin inhibitors block the conversion of angiotensinogen to ATI, the precursor to the biologically active vasoconstrictor ATII [2] . ACEIs block the conversion of ATI to ATII and preserve the vasodilating and cough-producing bradykinin. ARBs block ATII effects at the ATII type 1 receptor regardless of whether or not they were produced by ACE or other enzymes, and they do not alter bradykinin concentrations. Since the drug classes have similar but unique mechanisms of action, determining the comparative effectiveness of these drug classes is important [2] . Methods & results
In the current paper, the Duke Evidence-Based Practice Center (Durham, NC, USA) performed a comparative effectiveness review. Powers et al. used rigorous comparative effectiveness review methodology developed and vetted by Evidence-Based Practice Centers across the country [3] . They performed a broad search throughout December 2010. The authors limited their literature base to direct comparative studies of ACEIs, ARBs and/or DRIs that had at least 20 patients and reported on an outcome of interest. Ninety seven studies directly comparing ACEIs to ARBs were included in the comparative effectiveness review but only three studies directly compared an ACEI (n = 2) or ARB (n = 1) to a DRI. They allowed studies of fixed-dose com‑ bination medications, providing the non-renin–AT system medication and dose was standardized across the comparator groups (e.g., ACEI plus hydrochlorothizide
10.2217/CER.12.2 © 2012 Future Medicine Ltd
1(2), 125–127 (2012)
part of
ISSN 2042-6305
125
Priority paper evaluation
White
25 mg vs ARB plus hydrochlorothiazide 25 mg). The studies had to either be conducted entirely in a hypertensive population or the study had to report results in the hypertensive subpopulation separately. All of the results were given strength of evidence ratings using rigorously defined cri‑ teria with ‘high’ denoting high confidence in the results and that future studies are unlikely to change the conclusions, ‘low’ denoting poor con‑ fidence in the results and that future trials may well change the conclusions, ‘moderate’ denoting moderate confidence, and ‘insufficient’ denot‑ ing the inability to make a conclusion given the literature available. ACEIs and ARBs were found to have simi‑ lar long-term effects on blood pressure control (strength of evidence: high), rate of achieving the clinical trial specified blood pressure goal (odds ratio [OR]: 1.08; 95% CI: 0.94–1.25; strength of evidence: high), occurrence of mortality or major cardiovascular events (strength of evi‑ dence: low, out of the 38,589 subjects included only 38 deaths and 13 strokes were reported), impact on intermediate outcomes such as lipid and hemoglobin A1c concentrations (strength of evidence: moderate), or progression of renal disease by serum creatinine or urine albumin (strength of evidence: moderate). Based on very sparse literature, DRIs had a greater reduction in blood pressure than the ACEI ramipril and similar blood pressure control compared with the ARB losartan (strength of evi‑ dence: low). No conclusions could be drawn for the comparisons of DRIs with ACEIs and ARBs on the other aforementioned outcomes (strength of evidence: insufficient). ACEIs had a higher incidence of cough (OR: 4.74; 95% CI: 3.56–6.31) and withdraw‑ als due to adverse events (OR: 1.77; 95% CI: 1.42–2.21) than ARBs (strength of evidence for both outcomes: high); however, treatment adher‑ ence of those remaining in the trials was simi‑ lar between the two groups based on pill count (strength of evidence: moderate). DRIs had a lower incidence of cough (OR: 0.33; 95% CI: 0.22–0.49) and similar incidence of withdrawals (OR: 0.89; 95% CI: 0.46–1.71) versus ACEIs (strength of evidence: insufficient and low, respectively). There were no differences in the incidence of any other evaluated adverse event between any comparative group in this compara‑ tive effectiveness review. Angioedema was very rare, occurring in five patients receiving ACEIs, one patient receiving a DRI and no patients
126
J. Compar. Effect. Res. (2012) 1(2)
receiving an ARB (strength of evidence for a dif‑ ference between ACEI vs ARB: low; strength of evidence for ACEI or ARB vs DRI: insufficient). Sufficient data evaluating the comparative effectiveness of ACEIs, ARBs and DRIs for aforementioned outcomes in patient subgroups (based on ethnicity, gender or comorbidities) were lacking (strength of evidence: insufficient). Discussion
Similar to direct comparative trials in patients with stable ischemic heart disease, postmyocardial infarction with left ventricular dys‑ function and chronic heart failure, the benefits derived from ACEIs and ARBs in patients with hypertension are similar [4,5] . Direct compara‑ tive trial data are much more compelling than trying to cross extrapolate results of placebocontrolled trials because the underlying treat‑ ment of ischemic heart disease and cardiovascu‑ lar disease risk factors has changed dramatically over time, in addition to differences in study populations. The case can be made for using ACEIs preferentially over ARBs given the more extensive experience with this class of drugs and the comparative lower cost of therapy. In this scenario, the clinician would readily switch patients who experience ACE-induced cough to an ARB before considering a DRI. The data on DRIs in this comparative effec‑ tiveness review are derived from a very small number of trials without long-term followup. The ALTITUDE trial compared the DRI aliskerin in addition to ACEIs or ARBs versus ACEIs or ARBs alone [101] . While this trial would not have met the inclusion criteria for this comparative effectiveness review, it was stopped prematurely in December 2011, when the data safety monitoring board found and increased risk of nonfatal stroke, renal com‑ plications, hyperkalemia and hypotension over 18–24 months of follow-up with DRI plus ACEI or ARB versus ACE or ARB alone. This does not prove that DRI monotherapy versus an ACEI or ARB is more risky, but it does suggest that more experience with aliskerin is needed before its place in therapy can be established. The lowto-insufficient strength of evidence for DRIs in this comparative effectiveness review support this assertion. What this comparative effectiveness review does not do is provide an intraclass evaluation. While ACEIs and ARBs in their classes gener‑ ally work similarly, there are some nuances that
future science group
Comparative effectiveness of renin–angiotensin system inhibitors in hypertension
Priority paper evaluation
could lead a clinician to select one agent over another. For example, maximal dose losartan is not as effective as other ARBs (irbesartan and candesartan) in maximal doses and it is a CYP2C9 substrate. Captopril and lisinopril are not prodrugs and do not require hepatic acti‑ vation, while monopril has compensatory dual routes of elimination and has more standard dosing in renal impairment [2,6] .
than an ACEI, for example. Pharmacologically, ACEI-induced bradykinin preservation leads to vasodilation due to release of vasodilator pros‑ taglandins. Future trials comparing the DRIs to ACEIs and ARBs with an extended period of follow-up and a sample size sufficient to deter‑ mine its effects on final health outcomes and adverse effects is needed to determine its role in therapy.
Future perspective
Financial & competing interests disclosure
What would be most helpful to clinicians is an individual patient data meta-analysis. In this type of evaluation, original patient data from the major clinical trials comparing ACEIs to ARBs are used to evaluate end points in sub‑ groups by gender, ethnicity and comorbidities. While the overall population has similar efficacy, this does not mean that those receiving higher dose NSAIDs may not do better on an ARB
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Executive summary In patients with hypertension, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers provide similar blood pressure effects and no differences were seen in final health outcomes. ■■ Angiotensin receptor blockers have less ACEI-induced cough and fewer withdrawals due to adverse events. ■■ Direct renin inhibitors have not been extensively studied versus ACEIs and angiotensin receptor blockers, and their role in therapy is less clear. ■■
References 1
2
3
Lewington S, Clarke R, Qizilbash N et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-ana lysis of individual data for one million adults in 61 prospective studies. Lancet 366, 2026–2033 (2005).
inhibitors for patients with essential hypertension: much more data, little new information. J. Gen. Intern. Med. doi:10.1007/s11606-011-1938-8 (2012) (Epub ahead of print). 4
Song JC, White CM. Pharmacologic, pharmacokinetic, and therapeutic differences among angiotensin II receptor antagonists. Pharmacotherapy 20, 130–139 (2000). Powers BJ, Coeytaux RR, Dolor RJ et al. Updated report on comparative effectiveness of ACE inhibitors, ARBs, and direct renin
future science group
5
Baker WL, Coleman CI, Kluger J et al. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers for ischemic heart disease. Ann. Intern. Med. 151, 861–871 (2009). White CM. Angiotensin-converting-enzyme inhibition in heart failure or after
www.futuremedicine.com
myocardial infarction. Am. J. Health Syst. Pharm. 57, s18–s25 (2000). 6
White CM. Pharmacologic, pharmacokinetic, and therapeutic differences among ACE inhibitors. Pharmacotherapy 18, 588–599 (1998).
■■ Website 101 Wood S. ALTITUDE halted: adverse
events when aliskerin added to ACE, ARB therapy. www.theheart.org/article/1331173 (Accessed 5 January 2012)
127
PRIORITY PAPER EVALUATION
Comparative effectiveness of renin–angiotensin system inhibitors in hypertension C Michael White Evaluation of: Powers BJ, Coeytaux RR, Dolor RJ et al. Updated report on comparative effectiveness of ACE inhibitors, ARBs, and direct renin inhibitors for patients with essential hypertension: much more data, little new information. J. Gen. Intern. Med. doi:10.1007/s11606-011-1938-8 (2012) (Epub ahead of print). Hypertension is a chronic problem in the USA and there are three main ways to block the renin–angiotensin system: direct renin inhibitors, angiotensinconverting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). This article is a summary of a direct comparative effectiveness review of direct comparative trials in patients with hypertension. In patients with hypertension, ACEIs and ARBs provide similar blood pressure effects and no differences were seen in final health outcomes. ARBs have less ACE-induced cough and fewer withdrawals due to adverse events. Direct renin inhibitors versus ACE inhibitors or ARBs have not been extensively studied and their role is less clear.
University of Connecticut School of Pharmacy, 80 Seymour Street, Hartford, CT 06102-5037, USA Tel.: +1 860 545 2469 Fax: +1 860 545 2277 [email protected]
Keywords: angiotensin-converting enzyme inhibitor n angiotensin receptor blocker n direct comparison n hypertension n renin inhibitor
Approximately 75 million Americans have hypertension, which can be treated with a myriad of medications including diuretics, b‑blockers, calcium-channel blockers and renin–angiotensin (AT) system inhibitors [1] . Renin–AT system inhibitors include direct renin inhibitors (DRIs), AT-converting enzyme inhibitors (ACEIs) and AT receptor blockers (ARBs). Renin inhibitors block the conversion of angiotensinogen to ATI, the precursor to the biologically active vasoconstrictor ATII [2] . ACEIs block the conversion of ATI to ATII and preserve the vasodilating and cough-producing bradykinin. ARBs block ATII effects at the ATII type 1 receptor regardless of whether or not they were produced by ACE or other enzymes, and they do not alter bradykinin concentrations. Since the drug classes have similar but unique mechanisms of action, determining the comparative effectiveness of these drug classes is important [2] . Methods & results
In the current paper, the Duke Evidence-Based Practice Center (Durham, NC, USA) performed a comparative effectiveness review. Powers et al. used rigorous comparative effectiveness review methodology developed and vetted by Evidence-Based Practice Centers across the country [3] . They performed a broad search throughout December 2010. The authors limited their literature base to direct comparative studies of ACEIs, ARBs and/or DRIs that had at least 20 patients and reported on an outcome of interest. Ninety seven studies directly comparing ACEIs to ARBs were included in the comparative effectiveness review but only three studies directly compared an ACEI (n = 2) or ARB (n = 1) to a DRI. They allowed studies of fixed-dose com‑ bination medications, providing the non-renin–AT system medication and dose was standardized across the comparator groups (e.g., ACEI plus hydrochlorothizide
10.2217/CER.12.2 © 2012 Future Medicine Ltd
1(2), 125–127 (2012)
part of
ISSN 2042-6305
125
Priority paper evaluation
White
25 mg vs ARB plus hydrochlorothiazide 25 mg). The studies had to either be conducted entirely in a hypertensive population or the study had to report results in the hypertensive subpopulation separately. All of the results were given strength of evidence ratings using rigorously defined cri‑ teria with ‘high’ denoting high confidence in the results and that future studies are unlikely to change the conclusions, ‘low’ denoting poor con‑ fidence in the results and that future trials may well change the conclusions, ‘moderate’ denoting moderate confidence, and ‘insufficient’ denot‑ ing the inability to make a conclusion given the literature available. ACEIs and ARBs were found to have simi‑ lar long-term effects on blood pressure control (strength of evidence: high), rate of achieving the clinical trial specified blood pressure goal (odds ratio [OR]: 1.08; 95% CI: 0.94–1.25; strength of evidence: high), occurrence of mortality or major cardiovascular events (strength of evi‑ dence: low, out of the 38,589 subjects included only 38 deaths and 13 strokes were reported), impact on intermediate outcomes such as lipid and hemoglobin A1c concentrations (strength of evidence: moderate), or progression of renal disease by serum creatinine or urine albumin (strength of evidence: moderate). Based on very sparse literature, DRIs had a greater reduction in blood pressure than the ACEI ramipril and similar blood pressure control compared with the ARB losartan (strength of evi‑ dence: low). No conclusions could be drawn for the comparisons of DRIs with ACEIs and ARBs on the other aforementioned outcomes (strength of evidence: insufficient). ACEIs had a higher incidence of cough (OR: 4.74; 95% CI: 3.56–6.31) and withdraw‑ als due to adverse events (OR: 1.77; 95% CI: 1.42–2.21) than ARBs (strength of evidence for both outcomes: high); however, treatment adher‑ ence of those remaining in the trials was simi‑ lar between the two groups based on pill count (strength of evidence: moderate). DRIs had a lower incidence of cough (OR: 0.33; 95% CI: 0.22–0.49) and similar incidence of withdrawals (OR: 0.89; 95% CI: 0.46–1.71) versus ACEIs (strength of evidence: insufficient and low, respectively). There were no differences in the incidence of any other evaluated adverse event between any comparative group in this compara‑ tive effectiveness review. Angioedema was very rare, occurring in five patients receiving ACEIs, one patient receiving a DRI and no patients
126
J. Compar. Effect. Res. (2012) 1(2)
receiving an ARB (strength of evidence for a dif‑ ference between ACEI vs ARB: low; strength of evidence for ACEI or ARB vs DRI: insufficient). Sufficient data evaluating the comparative effectiveness of ACEIs, ARBs and DRIs for aforementioned outcomes in patient subgroups (based on ethnicity, gender or comorbidities) were lacking (strength of evidence: insufficient). Discussion
Similar to direct comparative trials in patients with stable ischemic heart disease, postmyocardial infarction with left ventricular dys‑ function and chronic heart failure, the benefits derived from ACEIs and ARBs in patients with hypertension are similar [4,5] . Direct compara‑ tive trial data are much more compelling than trying to cross extrapolate results of placebocontrolled trials because the underlying treat‑ ment of ischemic heart disease and cardiovascu‑ lar disease risk factors has changed dramatically over time, in addition to differences in study populations. The case can be made for using ACEIs preferentially over ARBs given the more extensive experience with this class of drugs and the comparative lower cost of therapy. In this scenario, the clinician would readily switch patients who experience ACE-induced cough to an ARB before considering a DRI. The data on DRIs in this comparative effec‑ tiveness review are derived from a very small number of trials without long-term followup. The ALTITUDE trial compared the DRI aliskerin in addition to ACEIs or ARBs versus ACEIs or ARBs alone [101] . While this trial would not have met the inclusion criteria for this comparative effectiveness review, it was stopped prematurely in December 2011, when the data safety monitoring board found and increased risk of nonfatal stroke, renal com‑ plications, hyperkalemia and hypotension over 18–24 months of follow-up with DRI plus ACEI or ARB versus ACE or ARB alone. This does not prove that DRI monotherapy versus an ACEI or ARB is more risky, but it does suggest that more experience with aliskerin is needed before its place in therapy can be established. The lowto-insufficient strength of evidence for DRIs in this comparative effectiveness review support this assertion. What this comparative effectiveness review does not do is provide an intraclass evaluation. While ACEIs and ARBs in their classes gener‑ ally work similarly, there are some nuances that
future science group
Comparative effectiveness of renin–angiotensin system inhibitors in hypertension
Priority paper evaluation
could lead a clinician to select one agent over another. For example, maximal dose losartan is not as effective as other ARBs (irbesartan and candesartan) in maximal doses and it is a CYP2C9 substrate. Captopril and lisinopril are not prodrugs and do not require hepatic acti‑ vation, while monopril has compensatory dual routes of elimination and has more standard dosing in renal impairment [2,6] .
than an ACEI, for example. Pharmacologically, ACEI-induced bradykinin preservation leads to vasodilation due to release of vasodilator pros‑ taglandins. Future trials comparing the DRIs to ACEIs and ARBs with an extended period of follow-up and a sample size sufficient to deter‑ mine its effects on final health outcomes and adverse effects is needed to determine its role in therapy.
Future perspective
Financial & competing interests disclosure
What would be most helpful to clinicians is an individual patient data meta-analysis. In this type of evaluation, original patient data from the major clinical trials comparing ACEIs to ARBs are used to evaluate end points in sub‑ groups by gender, ethnicity and comorbidities. While the overall population has similar efficacy, this does not mean that those receiving higher dose NSAIDs may not do better on an ARB
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Executive summary In patients with hypertension, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers provide similar blood pressure effects and no differences were seen in final health outcomes. ■■ Angiotensin receptor blockers have less ACEI-induced cough and fewer withdrawals due to adverse events. ■■ Direct renin inhibitors have not been extensively studied versus ACEIs and angiotensin receptor blockers, and their role in therapy is less clear. ■■
References 1
2
3
Lewington S, Clarke R, Qizilbash N et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-ana lysis of individual data for one million adults in 61 prospective studies. Lancet 366, 2026–2033 (2005).
inhibitors for patients with essential hypertension: much more data, little new information. J. Gen. Intern. Med. doi:10.1007/s11606-011-1938-8 (2012) (Epub ahead of print). 4
Song JC, White CM. Pharmacologic, pharmacokinetic, and therapeutic differences among angiotensin II receptor antagonists. Pharmacotherapy 20, 130–139 (2000). Powers BJ, Coeytaux RR, Dolor RJ et al. Updated report on comparative effectiveness of ACE inhibitors, ARBs, and direct renin
future science group
5
Baker WL, Coleman CI, Kluger J et al. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers for ischemic heart disease. Ann. Intern. Med. 151, 861–871 (2009). White CM. Angiotensin-converting-enzyme inhibition in heart failure or after
www.futuremedicine.com
myocardial infarction. Am. J. Health Syst. Pharm. 57, s18–s25 (2000). 6
White CM. Pharmacologic, pharmacokinetic, and therapeutic differences among ACE inhibitors. Pharmacotherapy 18, 588–599 (1998).
■■ Website 101 Wood S. ALTITUDE halted: adverse
events when aliskerin added to ACE, ARB therapy. www.theheart.org/article/1331173 (Accessed 5 January 2012)
127
