Major guidelines suggest the use of either ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) as first line treatment in hypertensive patients with diabetes when cost is not a concern. However, there are few head to head trials of these agents and the difference in their protective effects in patients with diabetes remains inconclusive. There is also no consensus about the choice of treatments for combination therapy.
In this systematic review and bayesian network meta-analysis, researchers evaluated the effects of different classes of renin-angiotensin system blockers and other antihypertensive agents, including monotherapy and combination therapy, on survival and major renal outcomes in patients with diabetes [Bayesian network meta-analysis combines both direct and indirect evidence for multiple treatments comparisons to estimate the interrelations across all treatments, thus allowing analysis of RCT data for comparisons of multiple treatments, without breaking randomisation of treatments within each trial]. The review included 63 studies (n=36,917) which evaluated 11 different antihypertensive treatment regimens, including placebo. Death from any cause was reported in 2400 of 36,810 patients from 62 studies. End stage renal disease occurred in 766 of 25,813 patients from 19 studies. Doubling of serum creatinine levels was noted in 1099 subjects from 13 studies providing data on 25,055 patients.
The following findings were reported:
Effects of antihypertensive treatments on all cause mortality
• Compared with placebo, only β blockers showed a significant difference in all cause mortality (odds ratio 7.13, 95% credible interval, 1.37 to 41.39).
• Compared with β blockers, combination of ACEI plus calcium channel blocker [CCB] (0.067, 0.008 to 0.559) yielded the most significant effect on reducing mortality, followed by ACEI plus diuretic (0.121, 0.020 to 0.658), ACEIs (0.137, 0.023 to 0.711), placebo (0.140, 0.024 to 0.732), CCBs (0.145, 0.025 to 0.728), and ARBs (0.153, 0.025 to 0.793).
• Except for β blockers, the differences between treatments, such as ACEIs versus ARBs, were not significant.
• Although the protective effect of ACEI plus CCB vs. placebo was not statistically significant (0.51, 0.15 to 1.35), ACEI plus CCB had the greatest probability (73.9%) for being the best treatment option on reducing mortality followed by ACEI plus diuretic (46.0%) and ACEIs (24.5%); whereas ARBs showed the highest probability (35.3%) of being ranked at the sixth position. β blockers showed the worst ranking compared with other treatments (69.4% probability of being in the last position). There were extremely wide credible intervals for ARB plus CCB, ARB plus diuretic, and ACEI plus ARB, indicating great uncertainty in the estimation of treatment effect owing to small patient numbers and rare death events among those treatment arms.
Effects of antihypertensive treatments on end stage renal disease
• All comparisons among treatments showed no statistical significance in this outcome.
• For reducing the incidence of end stage renal disease, ACEIs showed a higher probability of being at the top two ranking positions (29.6%, 37.5%, respectively), closely followed by ARBs (26.6%, 35.0%, respectively), whilst the combination of ACEI plus diuretic was the treatment with the highest probability (41.9%) of being in the last ranking position.
Effects of antihypertensive treatments on doubling of serum creatinine levels
• ACEIs showed statistical significance in reducing incidence of doubled serum creatinine levels compared with either placebo (0.58, 0.32 to 0.90) or β blockers (0.12, 0.02 to 0.74). Other treatment strategies, such as ACEIs vs. ARBs, did not show significant differences.
• ACEIs showed the greatest probability (79.5%) of being the best treatment, followed by ARBs with the highest probability (63.7%) of being ranked the second whilst β blockers had the highest probability (88.9%) of being in the last ranking position.
The researchers point out that for reduction in mortality, therapy using the combination of ACEI with CCB showed the highest probability of being the best treatment, and this result was fairly robust across all sensitivity analyses. Nevertheless, since only 1.7% of the study participants were randomised to this combination, interpretation of the results should still be cautious in regards to external generalisability. In addition, many of the included studies showed low or even no events in one or both treatment arms, which increases the uncertainty in the comparisons of multiple treatments within a network meta-analysis; this is why the analyses showed wide credible intervals for several treatment comparisons. They conclude that the available evidence is not able to show a better protective effect for ARBs compared with ACEIs, so considering the cost of drugs, these findings support the use of ACEIs as the first line antihypertensive agent in patients with diabetes, whilst CCBs might be the preferred treatment in combination with ACEIs if adequate blood pressure control cannot be achieved by ACEIs alone.
The NICE guideline on hypertension makes the following recommendations:
• Offer an ACEI or a low-cost ARB as initial treatment for people aged under 55 years, but if an ACEI is not tolerated, a low-cost ARB can be tried.
• A CCB should be offered to people aged over 55 years and to black people of African or Caribbean family origin of any age, but if it is not suitable, offer a thiazide-like diuretic.
• β blockers are not a preferred initial therapy for hypertension, however, they may be considered in younger people, particularly: those with an intolerance or contraindication to ACEIs and ARBs or women of child-bearing potential or people with evidence of increased sympathetic drive.
• If therapy is initiated with a β blocker and a second drug is required, add a CCB rather than a thiazide-like diuretic.
• If blood pressure is not controlled by step 1 treatment, offer step 2 treatment with a CCB in combination with either an ACEI or an ARB.
• If a CCB is not suitable for step 2 treatment, offer a thiazide-like diuretic.
• For black people of African or Caribbean family origin, consider an ARB in preference to an ACEI in combination with a CCB.
• If treatment with three drugs is required, the combination of ACEI or ARB, CCB and thiazide-like diuretic should be used.