Outcomes
An overview of patients’ outcomes by interventions is presented in (Supplemental, Table 2).
Efficacy (Fig. 2)
The main outcome of interest was the difference in the mean blood pressure after the follow-up period. All four (Cushmann 20125, Neutel 201711, Cushmann 201812 and Bakris 201813) studies reported the mean systolic and diastolic blood pressure. The analyses showed that the patients in the AZI-M/CT group had a lower SBP than those in the OLM/HCTZ group (WMD –2.95 [-6.64,0.73]; p= 0.12, I2=100%). Similarly, the DBP was also found to be lower in the AZI-M/CT group (WMD –2.64 [-2.78, -2.51]; p= <0.00001, I2= 1%). Additionally, the number of patients who achieved target blood pressure was reported by three out of four studies (Cushmann 20125, Cushmann 201812 and Bakris 201813). Our study showed that there was no significant difference between the two groups in terms of achievement of target blood pressure (RR 0.95 [0.84,1.07]; p= 0.36, I2= 80%).
Adverse events (Fig.3)
All four studies (Cushmann 20125, Neutel 201711, Cushmann 201812 and Bakris 201813) reported adverse events. The pooled analysis showed that the patients in the AZI-M/CT group had a significantly higher risk of any TEAE than the patients in the OLM/HCTZ group (RR 1.11 [1.03,1.20]; p= 0.007, I2= 51%). Moreover, our study showed that the risk of serious adverse events was significantly higher in the AZI-M/CT group (RR 1.58 [1.20,2.08]; p= 0.001, I2= 11%). Of all the signs and symptoms reported only dizziness was found to be significantly higher in the AZI-M/CT group (RR 1.40 [1.12, 1.74; p = 0.003, I2= 43%), whereas no significant association was found between headache (RR 0.76 [0.51,1.14; p = 0.19, I2= 43%), fatigue (RR 1.41 [0.97,2.04; p = 0.07, I2= 0%). and the two groups.
Only two studies (Cushmann 201812 and Bakris 201813) reported the data on diarrhoea and hypotension. No significant association was found between diarrhoea ((RR 0.99 [0.10,9.79; p = 1.00, I2= 74%), hypotension (RR 1.80 [0.54,5.97; p = 0.34, I2= 0%) and the two groups.
Mortality (Fig. 4)
Only two out of four studies (Neutel 201711 and Bakris 201813) documented the data for mortality. However, the pooled analysis showed that the risk of death was lower in the patients treated with AZI-M/CT than the patients treated with OLM/HCTZ (RR 0.74 [0.14,3.91; p = 0.72, I2= 0%).
Laboratory parameters (Fig. 5)
All four studies (Cushmann 20125, Neutel 201711, Cushmann 201812 and Bakris 201813) reported hyperuricemia, hypokalaemia, and increased Creatinine. Of these outcomes, the risk of Hyperuricemia (RR 01.90 [1.43,2.53; p = < 0.0001, I2= 36%), and rise in the Creatinine values (RR 1.79 [1.26,2.54; p = 0.001, I2= 70%) was found to be significantly higher in the AZI-M/CT group, whereas no significant association was found between Hypokalaemia (RR 1.43 [0.78,2.62; p = 0.24, I2= 0%) and either of the two groups.
Three out of four studies (Cushmann 20125, Neutel 201711, Cushmann 201812) reported the data on the following outcomes: the risk of change in the levels of sodium from normal to low was found to be significantly higher in the AZI-M/CT group (RR 2.23 [1.24,4.04; p = 0.008.72, I2= 0%), whereas no significant association was found between fasting glucose shift from <7.0 to ≥7.0 mmol/L (RR 1.00 [0.76,1.30; p = 0.98, I2= 0%), 2 consecutive elevations (1.5 baseline and >ULN) of Creatinine (RR 1.44 [0.49,4.26; p = 0.51, I2= 73%) and the two groups.
Only two studies (Cushmann 20125 and Neutel 201711) reported the data on the shift of fasting glucose Shift from ≥7.0 to <7.0 mmol/L, and the results showed no significant association between the shift in fasting glucose from ≥7.0 to <7.0 mmol/L and the two groups (RR 1.43 [0.72, 2.88; p = 0.31, I2= 55%).
Leave one out sensitivity analysis (Fig 6)
Due to high heterogeneities in the pooled analysis of mean systolic blood pressure and the number of patients who achieved target blood pressure, a leave one out analysis was performed. According to the results, exclusion of Cushmann 20185 and Bakris 201813 individually substantially affected the mean systolic blood pressure, whereas exclusion of Bakris 201813 substantially influenced the results of achievement of target blood pressure.
DISCUSSION
This comprehensive systematic review and meta-analysis of 4 studies comprising of 3146 patients compared outcomes with AZI-M/CT to OLM/HCTZ in hypertensive patients. Both drugs were able to achieve the target BP, which is less than 140/90 mmHg, or <130/80 mm Hg for those with diabetes or chronic kidney disease14. In fact, AZI-M/CT generally showed a higher efficacy at the same doses compared to OLM/HCTZ, causing generally greater decreases in BP, especially significant decreases in DBP across the studies. Even though the decreases in SBP were found to be insignificant, minor reductions can still lead to various cardiovascular benefits. For instance, in middle aged adults, an SBP reduction of 2 mmHg can lead to a 10% lower stroke mortality and around a 7% decreased risk of mortality from ischemic heart disease15. Both treatments were mostly tolerated, though AZI-M/CT was found to have higher treatment‐emergent adverse events (TEAEs), especially dizziness. However, majority of these were mild or moderate effects that were more commonly found in the higher dosage formulations. Similarly, higher doses of AZI-M/CT were also associated with higher rates of serious AEs and discontinuations. It should be noted that many of these discontinuations were likely because of patients being withdrawn from treatment, as advised by protocol guidance, due to high serum creatinine.
Creatinine levels were significantly higher in patients belonging to the AZI-M/CT group. Nevertheless, these increases were reversible on cessation of therapy, and reflected more of a physiological effect owing to the mechanism of the drugs rather than an adverse effect. In fact, in patients with renal disease who are prescribed ARBs, it is common for serum creatinine to rise to 35% above baseline as blood pressure decreases16. Indeed, higher reductions in blood pressure would be associated with greater increases in creatinine, thereby reflecting drug efficacy. ARBs inhibit the renin-angiotensin-aldosterone axis17. The decrease in angiotensin-II allows for vasodilation of the efferent arterioles in the glomeruli, increasing renal blood flow whilst reducing glomerular filtration rate, leading to an increase in various blood metabolites such as urea and creatinine17. This effect can be exacerbated in patients with chronic hypertension who are less able to autoregulate renal blood flow due to endothelial dysfunction18. When potent diuretics, such as CLD are concomitantly used, volume contraction of blood may occur that can further exaggerate creatinine elevation17.
This greater efficacy of AZI-M/CT is likely due to the individual benefits of both the component drugs. White et al19 compared the effects of AZI-M against Olmesartan medoxomil (OLM) and valsartan (VAL). The study found that 80 mg of AZI-M caused a significantly lower reduction in 24 hours mean SBP compared to maximum clinically approved dosages of OLM (40 mg) and VAL (320 mg), while not being associated with any significant increase in AEs19. This higher efficacy maybe explained in part by its greater binding affinity to the angiotensin receptor, compared to other ARBs20. AZI-M has also been found to be more effective than other diuretics, specifically angiotensin-converting enzyme inhibitors (ACE-I) at reducing BP, while also having the same or fewer side effects, most notably dry cough. These benefits would effectively lead to better treatment compliance20. CT has a longer half-life, thus retaining its hypertensive efficacy for longer (47 – 72 hours) compared to HCTZ (16 – 24 hours)21. This allows for CT to have comparable reductions to HCTZ in office SBP, superior reductions in 24-hr ambulatory BP, and lower night-time BP21. However, a recent observational study found no significant differences between CT and HCTZ in cardiovascular outcomes, namely acute myocardial infarction, hospitalized heart failure, or stroke4. Additionally, CT use is associated with a high risk of hypokalemia, and other electrolyte abnormalities, making HCTZ the preferred drug. However, when lower doses of CT are used in combination with an ARB, notably AZI-M, the incidence of hypokalemia and other electrolyte abnormalities decreases and becomes comparable to those of OLM/HCTZ5,13.
LIMITATIONS
This meta-analysis has a few limitations that should be considered while interpreting the results. First, differences in study designs, interventions, and patient characteristics such as body weight, age, sample sizes and gender ratios present in the patient population, and differences in trial characteristics may have contributed to clinical heterogeneity. Second, the follow up ranges for most studies were variable, with some studies reporting longer follow up periods. Short term follow ups are more useful when evaluating disease prognosis. Conversely, long-term prognosis can overestimate progress by showing better recovery or can show worse decline in health. Third, some drugs/dose combination may have limited power compared to others.
CONCLUSION
Current systematic review and meta-analysis suggests that AZI-M/CT is the better treatment compared to OLM/HCTZ in lowering BP in elderly hypertensive patients. Larger clinical trials comparing efficacy and safety profiles of AZI-M/CT and OLM/HCTZ are warranted to affirm our results.
Declarations of interest
None
Disclosures
The authors report no proprietary or commercial interest in any product mentioned or concept discussed in the article.
Acknowledgements
None