Combining ACEI and ARB Therapy: The Next Step?

Pharmacokinetic rationale for combination ACEI and ARB therapy Although ACEIs and ARBs exert protective effects against CVD and renal damage, the difference in their mechanisms may have important clinical implications. Combination therapy leads to enhanced accumulation of bradykinin and thereby to increased NO generation and enhanced vasodilation. ARBs avoid the problem of angiotensin II escape; whereas, the AT1 receptor mediates most of the pathophysiologic actions of angiotensin II, the AT2 receptor acts largely to counteract these effects; therefore, combination therapy may provide more complete blockade of angiotensin II. Not only could this lead to improved BP control, but it may also enhance the pleiotropic effects of these drugs. Potentially, dual ACEIs and ARBs offer additive clinical benefits in patients including those with HF or diabetic kidney disease.

Key biochemical and hormonal effects of dual RAAS blockade Dual blockade of the RAAS combines the biochemical consequences of ACE inhibition and ARBs. Although the combination allows for more complete and sustained blockade of circulating and tissue RAAS, alternative mechanisms involving bradykinin and Ang (1-7) accumulation, AT2 receptor stimulation, and consequent NO release may participate in the overall pharmacodynamic effect. The ACEI and ARB combination will also moderate the impact of non-ACE induced production of angiotensin II. The combination of pharmacologic agents that inhibit ACE and the AT1 receptor can minimize or even overcome the escape observed with single-site ACE blockade.

ACEI-ARB combination vs ACEI monotherapy in ambulatory SBP: Meta-analysis Doulton et al conducted a meta-analysis to examine evidence for a greater decline in BP when combing an ACEI and ARB for the treatment of HTN. Multiple different combinations of ACEIs and ARBs were evaluated. Combination therapy had a small additive effect on BP reduction in hypertensive individuals compared with ACEI or ARB monotherapy. On this slide, the combination of an ACEI and an ARB reduced ambulatory BP by 4.7 mm Hg compared with ACEI monotherapy.

ACEI-ARB combination vs ARB monotherapy in ambulatory SBP: Meta-analysis Doulton et al also found that the combination of an ACEI and an ARB reduced ambulatory systolic BP by 3.8 mm Hg compared with ARB monotherapy. Data on 8 trials indicated that the combination of an ACEI and an ARB reduced proteinuria by 30% compared with ACEI monotherapy and by 39% compared with ARB monotherapy. In the majority of the studies reviewed, there were no significant changes in serum potassium or hemoglobin. A large acute deterioration in renal function was reported in just 1 patient in the 14 studies reviewed.

Meta-analysis: ACEI + ARB reduces proteinuria compared with monotherapy (1 to 4 months) A meta-analysis of randomized trials compared the effect of monotherapy with ACEI and ARB with the combination of ACEIs and ARBs on proteinuria in patients with microalbuminuria and proteinuria, with or without diabetes. The combination of the two drugs was more effective in reducing proteinuria than either drug alone at usual doses. Results at 1 to 4 months are shown here. Despite these promising findings the authors commented that uncertainty concerning adverse effects and outcomes that are important to patients (including, end-stage renal disease) limit the implications of these results for clinical practice. Long-term trials are necessary to clarify the role of combination therapy versus ACEI or ARB monotherapy in patients with proteinuria who are representative of those seen in clinical practice.

DETAIL: ARB and ACEI yield similar changes in GFR The Diabetics Exposed to Telmisartan and Enalapril (DETAIL) study randomly assigned 250 subjects with T2DM and early nephropathy to receive either the ARB telmisartan (80 mg daily) or the ACEI enalapril (20 mg daily). After 5 years, the change from baseline GFR (mL/min per 1.73 m2 was -17.5 with telmisartan as compared with -15.0 with enalapril, representing a difference of 2.6 (95% CI -7.1 to 2.0).(1) The results indicate that telmisartan is not inferior to enalapril in providing long-term renoprotection in persons with T2DM. 1. Barnett AH et al. N Engl J Med. 2004;351:1952-61; Corrections. N Engl J Med. 2005;352:1731

ACEI + ARB in HF The Valsartan Heart Failure Trial (Val-HeFT) compared the additive effects of valsartan on top of standard treatment in 5010 patients with CHF. Although mortality was unaffected, valsartan clearly reduced hospital admissions for worsening of CHF (valsartan 13.8% vs placebo 18.2%; relative risk [RR] 0.76, P < 0.001). CHARM-Added demonstrated both a reduction of CV mortality (RR 0.84, P = 0.029) and hospital admission for worsening of CHF (RR 0.83, P = 0.014). In VALIANT, the combination of valsartan and captopril did not further reduce all-cause mortality compared with captopril alone, but it demonstrated a significantly reduced incidence of hospital admissions for worsening of HF (RR 0.89, P = 0.005).

ACEI + ARB enhances regression of LV hypertrophy Suzuki et al assessed the effects of an ACEI, an ARB, and an ACEI and ARB combination, on the regression of LV hypertrophy in diabetic patients on dialysis therapy. Echocardiographic assessment of LV mass index was performed at baseline and after 6 and 12 months of treatment. Treatment with enalapril, losartan, and dual therapy was associated with significant reductions in LV mass index after 6 months and 1 year of treatment. At 1 year however, dual ACEI plus ARB resulted in an additional 28% reduction in LV mass index compared with either monotherapy (P < 0.05 vs enalapril and losartan).

RAAS inhibition in prevention of atrial fibrillation A meta-analysis of clinical trials, all randomized, examining the prevention of atrial fibrillation (AF), shows a 25% relative risk reduction with ACEIs. Pooled data from ARB trials show a 30% relative risk reduction in AF; the total relative risk reduction in AF with ACEIs and ARBs is 30%. However, when ACEI trials done in patients with LV dysfunction are excluded from the analysis, the results are no longer statistically significant; whereas, for the ARB trials that did not involve patients with LV dysfunction, the relative risk reduction is 42%. Further analysis of both ARB and ACEI trials, according to the underlying patient population, suggests that AF reduction with ACEIs and ARBs is likely to be greater in patients with LV dysfunction.

Meta-analysis: Adverse effects of ACEIs + ARBs in symptomatic LV dysfunction (LVD) The safety profile of combination ARB and ACEI therapy in patients with symptomatic LV dysfunction was assessed in a meta-analysis of 4 randomized clinical trials with 17,337 patients. The studies included ValHeFT, CHARM-Added, VALIANT, and the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD). The findings showed that in patients with CHF or with acute MI with LV dysfunction, greater vigilance with combination therapy should be shown with regard to decreased renal function (elevations in serum creatinine >0.5 mg/dL) or hyperkalemia (serum potassium levels >5.5 mEq/L). However, with regard to discontinuations or symptomatic hypotension, the confidence intervals are relatively wide, suggesting that the difference between combination therapy and controls is not great.

Risk of MI with ARBs vs ACEIs, other active drugs, and placebo There have been some reports that the use of ARBs might increase a patient’s risk of MI. The meta-analysis illustrated here explored the influence of ARBs on MI, analyzing all the major international, randomized trials using ARBs compared with another active drug or placebo. As shown, there were no significant differences in fatal and nonfatal MI between treatment with ARBs, placebo, or active treatment. The same result was obtained when considering only trials in which ARBs were compared with ACEIs, or when pooling all trials together. The pooled analysis of these trials shows no evidence of increased risk of MI in patients treated with ARBs; the relative risk of MI lies substantially on the indifference line.

ONTARGET/TRANSCEND trials: RAAS modulation after HOPE-the next chapter The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) was designed to determine if the combination of the ARB telmisartan and the ACEI ramipril is more effective than ramipril alone, and if telmisartan is at least as effective as ramipril in high-risk patients. The Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) was designed to determine if telmisartan is superior to placebo in patients who are intolerant of ACEIs. For both trials, the primary outcome was the composite of CV death, MI, stroke, or hospitalization for HF. The following slides describe these studies in further detail.

ONTARGET Overview: Substudies Seven substudies are embedded in the main trials: Ambulatory BP monitoring (ABPM) will be performed to determine its prognostic value and the effects of study medications. Cardiac magnetic resonance imaging (MRI) will be performed to examine effects of treatment on cardiac structure and function. The effect of treatment on erectile dysfunction will be assessed. Arterial stiffness will be estimated by pulse wave velocity to determine the effect telmisartan has on it. Biological samples will be collected at baseline for analysis of novel risk factors and CVD markers. An oral glucose tolerance test (OGTT) will be carried out in all TRANSCEND patients who are not known to have T2DM at baseline, and at 2 years follow-up and close-out. Health economics will be studied to determine resources use and direct medical costs associated with clinical events.

ONTARGET: Study design The ONTARGET study compared an ACEI vs an ARB vs a combination of both in high-risk individuals similar to those in the HOPE trial, ie, aged 55 years or older with a previous coronary artery, peripheral artery, or cerebrovascular event, or diabetes with evidence of target organ damage. Patients with uncontrolled hypertension on treatment (ie, BP >160/100 mm Hg) or symptomatic HF were excluded. The primary objectives of ONTARGET were to determine: If the combination of telmisartan 80 mg daily and ramipril 10 mg daily is more effective in reducing the composite outcome than ramipril 10 mg alone. Whether telmisartan 80 mg daily is at least as effective (ie, “not inferior”) as ramipril 10 mg daily as monotherapy. The secondary objectives were development of newly diagnosed HF, T2DM, or atrial fibrillation; the need for revascularization procedures, development of dementia/cognitive decline, and nephropathy.

ONTARGET: Baseline medical conditions vs HOPE By design, the patients enrolled in ONTARGET were comparable to those in HOPE; ie, they were at high risk for a CV event. A higher proportion of patients in ONTARGET had hypertension and cerebrovascular disease. Abbreviation: TIA = transient ischemic attack

ONTARGET: Baseline medications vs HOPE Use of aspirin was comparable in both trials. Use of other proven CV therapies (specifically, ACEIs, beta-blockers, and statins) was higher in ONTARGET.

ONTARGET: Time to primary outcome The primary outcome occurred in 16.5%, 16.7%, and 16.3% of patients in the ramipril, telmisartan, and combination groups, respectively. Hazard ratio for telmisartan vs ramipril 1.01, 95% CI 0.94-1.09 Hazard ratio for combination vs ramipril 0.99, 95% CI 0.92-1.07

Primary outcome of ONTARGET compared to HOPE The margin to determine noninferiority was based on the results of the HOPE trial. In that trial, the hazard ratio for the composite outcome used in ONTARGET (CV death, MI, stroke, or hospitalization for heart failure) was 0.775. However, for ONTARGET the value used was the 40th percentile (0.794), which translates into an excess risk for placebo vs ramipril of 1.26. Thus, an upper CI <1.13 ensured that telmisartan retained at least 50% of the effect of ramipril. The upper boundary of the CI for this outcome indicated noninferiority. The lower boundary indicated that telmisartan was not superior to ramipril. A similar result was obtained for the composite outcome of CV death, MI, or stroke. Adjustment for the small differences in blood pressure between the groups did not materially alter the results. Abbreviation: hosp = hospitalization

ONTARGET: Noninferiority comparison The slide graphically illustrates the results discussed in the previous slide.

ONTARGET: Combination vs ramipril in prespecified groups Comparisons of key subgroups showed similar results for the combination vs ramipril as observed for the overall population. Abbreviation: Hx = history

ONTARGET: Effects of telmisartan, ramipril, and combination on primary renal outcome In this prespecified analysis of renal outcomes, the primary outcome was the first occurrence of dialysis, doubling of serum creatinine, or death. The primary renal outcome was similar for telmisartan and ramipril alone (13.4% vs 13.5%, respectively), but was significantly increased with combination therapy (14.5%, P = 0.037 vs ramipril).

ONTARGET: Relative risk of primary renal outcome by subgroup: Telmisartan vs ramipril In the overall population, the hazard ratio for the primary renal outcome for telmisartan vs ramipril was 1.00, 95% CI 0.92-1.09. Telmisartan and ramipril had similar effects on the primary outcome in all subgroups studied.

ONTARGET: Relative risk of primary renal outcome by subgroup: Ramipril vs ramipril plus telmisartan In the overall population, the HR for the primary renal outcome for ramipril vs ramipril plus telmisartan was 1.09, 95% CI 1.01-1.18, P = 0.037. In subgroups at lower renal risk, combination therapy showed clear evidence of harm. However, the effect was less in subgroups at relatively high renal risk.

ONTARGET: Decline in eGFR with ramipril, telmisartan, and combination At 2 years follow-up, estimated glomerular filtration rate (eGFR, expressed as mL/min per 1.73 m[2]) decreased less with ramipril (-1.96) than with telmisartan (-3.05) or with combination therapy (-5.12; P < 0.0001 for both telmisartan and combination vs ramipril).

ONTARGET: Time to permanent discontinuation of study medication Study drug was discontinued in 23.7% and 21.0% of the ramipril and telmisartan groups, respectively.(1) However, at any time point, the discontinuation rate tended to be lower in the telmisartan group. In the combination group, 22.7% discontinued both drugs and a further 6.7% discontinued at least 1 drug (data not shown).(1) 1. ONTARGET Investigators. N Engl J Med. 2008;358:1547-59.

ONTARGET: Study medication discontinuation-telmisartan vs ramipril Compared with telmisartan, more patients discontinued ramipril because of cough or angioedema. Compared with ramipril, more patients discontinued telmisartan because of hypotensive symptoms.

ONTARGET: Study medication discontinuation-ramipril vs combination The slide summarizes the most important reasons for discontinuation in the ramipril and combination groups. Compared with ramipril, more patients in the combination therapy group stopped taking a study drug because of hypotensive symptoms, syncope, diarrhea, or renal impairment.

ONTARGET: Conclusions The study investigators concluded that telmisartan was noninferior to ramipril and was better tolerated. The combination of the two did not provide incremental benefit in reducing the primary outcome, and while it reduced proteinuria vs monotherapy, overall it worsened major renal outcomes. Careful monitoring of renal function and serum potassium is required if the two drugs are used together.

ONTARGET: Implications Based on the ONTARGET results, telmisartan appears to be an equally effective alternative to ramipril, with better tolerability. In the opinion of the investigators, choice between the two agents will depend on patient and physician preference as well as patient susceptibility to specific adverse events.

TRANSCEND: Study design The Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) was a placebo-controlled evaluation of telmisartan 80 mg in patients who were intolerant to ACEIs. ACEI intolerance was defined as previous discontinuation by a physician, with a specific documented cause. Other eligibility criteria included 55 years of age or older and coronary artery, peripheral vascular, or cerebrovascular disease, or diabetes with evidence of end-organ damage. The primary outcome was the composite of CV death, MI, stroke, and hospitalization for HF. This was the same primary outcome used in PRoFESS (discussed earlier in this slide kit) and a combined analysis of the two trials was prespecified.

TRANSCEND: Baseline medical conditions vs HOPE As with ONTARGET, by design, the patients enrolled in TRANSCEND were comparable to those in HOPE; ie, they were at high risk for a CV event. A higher proportion of patients in TRANSCEND had hypertension and cerebrovascular disease.

TRANSCEND: Baseline medications vs HOPE Use of aspirin was comparable in both trials. Use of other proven CV therapies (specifically, beta-blockers and statins) were higher in TRANSCEND.

TRANSCEND: Treatment effect on the primary outcome The primary outcome occurred in 15.7% and 17.0% of the telmisartan and placebo groups, respectively (hazard ratio 0.92, 95% CI 0.81-1.05, P = 0.216.

TRANSCEND: Treatment effect on components of primary outcome Consistent with the primary outcome, there was no statistically significant between-group difference in event rate for the individual components of this composite outcome.

TRANSCEND and PRoFESS combined results: Evidence for delayed benefit When the data were combined with PRoFESS and events classified as occurring either before or after 6 months, there was a significant reduction in the primary outcome events that occurred after 6 months: 10.3% (telmisartan) vs 11.7% (placebo), P < 0.001. There was no evidence of a beneficial effect on the primary outcome before 6 months.

TRANSCEND: Conclusions and implications Telmisartan was well tolerated in this population of high-risk, ACEI-intolerant patients. Fewer patients permanently discontinued treatment in the telmisartan group vs placebo: 21.6% vs 23.7%, respectively, P = 0.055. Among patients with cough as the initial reason for ACEI intolerance, discontinuation was infrequent in both groups: 0.54% vs 0.57%, respectively. However, reduction of CV events was modest and did not reach statistical significance. Analyses suggested that greater benefit might have been achieved with more prolonged treatment. The study investigators wrote, “In view of the drug’s tolerability and effects on cardiovascular endpoints, telmisartan could be regarded as a potential treatment for patients with vascular disease or high-risk diabetes, if they are unable to tolerate an ACE inhibitor.”

Evaluation of combined ACEI/ARB therapy: What the evidence shows Combination of an ACEI and ARB is associated with greater lowering of blood pressure than monotherapy alone. However, with regard to renal protection or cardiac protection, there is suggestive evidence of benefit over monotherapy only in selected subgroups. These findings need confirmation in other studies. Careful monitoring of renal function and serum potassium is required if the two drugs are used together.