The incidence and prevalence of end-stage renal disease (ESRD) has been constantly rising and costing many medical resources in dialysis and kidney transplantations. ESRD has become a global healthcare issue and a financial burden to many governments.1,2 The number of ESRD patients worldwide has increased at a rate of 7%.3 During the past 10 years, Taiwan has also confronted a serious challenge because the incidence and prevalence of ESRD have increased 2.6 and 3.7 times, respectively.2 Taiwan has had the greatest incidence and the second greatest prevalence of ESRD since 2000 in an international comparison based on data from the US Renal Data System.4
ESRD is primarily caused by chronic kidney disease (CKD). Many studies have confirmed that hypertension is 1 of the factors leading to the deterioration of kidney function. In addition, CKD is a common disease that tremendously affects the quality of life of individuals and significantly increases morbidity and mortality.5 Use of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) to block the rennin–angiotensin system is suggested to slow the progression of ESRD from CKD. However, even with the application of ACEi or ARB, many patients with CKD still progress to ESRD.6–14 This study provides an opportunity to reverse the persistent increase of ESRD incidence in Taiwan.
Due to the potential racial differences in drug effects, current available evidence alone might not ensure the clinical efficacy of drug application.15 Multiple studies have verified that ACEi and ARB demonstrate excellent kidney-protection effects regardless of whether these patients have type II diabetes mellitus (DM).6–14 A few clinical studies have shown that ACEi and ARB exhibit cardiovascular benefits in patients with kidney disease. However, these studies combined several endpoints to evaluate the ACEi and ARB therapeutic effects.9–12,14,15 Therefore, their findings were neither affirmative nor interpreted as final clinical results. It is necessary to conduct a large-scale study to confirm the association of ACEi and ARB therapy on reducing risks of mortality, reaching ESRD, or first hospitalization due to cardiovascular diseases (CVDs).
The National Health Insurance (NHI) program has been implemented in Taiwan for 20 years, and 99.8% of the total population (23.5 million people) is enrolled in the program.16 In addition, 93.4% of medical facilities signed contracts with the Bureau of NHI. This study used NHI Research Database (NHIRD) data to evaluate the association of losartan, ramipril, and conventional antihypertensive agents on the prognosis of hypertensive patients with CKD. Specifically, the first objective was to study whether losartan and ramipril could lower the incidence of ESRD progression from CKD regardless of whether the patients had DM or not; the second objective was to confirm whether losartan and ramipril could reduce the mortality of CKD patients; and the third objective was to determine whether losartan and ramipril could prolong the progression from CKD to ESRD or death.
The National Health Research Institute randomly selected a representative database from the NHI Database (NHID) to build NHIRD, which contains healthcare utilization data including sex, date of birth, diagnostic code, drug prescriptions, and medical procedures. The database of inpatient expenditures by admissions and ambulatory care expenditures by visits accounted for 5% and 0.2%, respectively, across the entire database. Ultimately, 1,000,000 insured subjects were randomly selected from NHID and accounted for 4.3% of the total population.16 This study was approved by the Institutional Review Board of the National Defense Medical Center, and informed consent was waived due to the personal information having been de-identified in the NHIRD.
Design and Participants
The study was designed as a population-based cohort study. Participants in this study were 18- to 70-year-old patients with CKD between 2001 and 2008. Participants were excluded due to missing sex or age information. The conventional group included patients who were only taking conventional antihypertensive medicines such as diuretics, beta-blockers, calcium channel blockers, alpha-blockers, and direct vasodilators without using ARB or ACEi. The losartan group included patients who were taking losartan alone or combined with conventional antihypertensive drugs as needed but without using other ARB or ACEi medicines. The ramipril group included patients who used ramipril alone or combined with conventional antihypertensive drugs as needed but without using other ACEi or ARB medicines.
Definition of CKD
The disease condition was defined according to the diagnostic code constructed by the Bureau of NHI based on the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM).17 We defined CKD cases as those with at least 1 CKD diagnostic code (ICD-9 codes 250.4*, 274.1*, 403.1*, 404.2*, 404.3*, 440.1, 442.1, 447.3, 572.4, 580–588, 642.1*, 646.2*) present in the service claim and those who had not reached the stage of ESRD.
The outcome variables included time to the first endpoint, incidence, and risk for the patients who were diagnosed with CKD. Endpoints were referred to as the following: ESRD (ICD-9 codes 39.95, 54.98, 55.69), all- and cardiovascular-cause mortality referred to as coronary heart disease (CHD) (ICD-9 codes 410**–414**), heart failure (ICD-9 codes 428*), and stroke (ICD-9 codes 430–438**) in this study, as well as hospitalization for the first time due to CVD. An incident case was defined as when the subject had hypertension and was not diagnosed with CKD in 2000 but was diagnosed with CKD between January 1, 2001 and December 31, 2008 and then was diagnosed with ESRD, died, or was first hospitalized due to CVD. Person-years of the participants indicated the period between the diagnosis of CKD using antihypertensive drugs and occurrence of an endpoint. ESRD was defined as the requirement for long-term dialysis or kidney transplantation.
Endpoints were analyzed according to the intention-to-treat principle. We used Cox's proportional hazard regression model to assess the incidence and risk of each endpoint. Hazard ratios (HRs) were calculated and adjusted for sex, age, CHD, stroke, heart failure, DM (ICD-9 code 250), dyslipidemia (ICD-9 code 272), obesity (ICD-9 code 278), and concomitant antihypertensive treatment. The degree of risk reduction was calculated as (1-HR) × 100%. We compared categorical and quantitative data between groups with the χ2 test and ANOVA, respectively. All statistics involved a 2-tailed test. A P value < 0.05 indicated statistical significance. Data were analyzed in SPSS (version 20; IBM., Armonk, NY, USA).
In total, 136,445 patients were assessed for eligibility, and 179 subjects were excluded due to missing sex (135 subjects) or age (44 subjects) information. The study cohort consisted of 136,266 individuals. The average and total follow-up time was 5.9 years (range: 0.1–7.8 years) and 803,006 person-years, respectively (Fig. 1); 7364 (5.40%) patients reached ESRD, 4165 (3.06%) patients died, and 6163 (4.52%) patients were first hospitalized due to CVD.
In total, 6377 patients were in the losartan group, among whom 335 (5.25%) patients reached ESRD, 185 (2.90%) patients died (89 patients died of CVD), and 281 (4.41%) patients were first hospitalized due to CVD; 2597 patients were included in the ramipril group, among whom 133 (5.12%) patients reached ESRD, 73 (2.81%) patients died (38 patient died of CVD), and 110 (4.24%) patients were first hospitalized due to CVD. In the conventional group, there were 127,292 patients. Of these patients, 6896 (5.42%) reached ESRD, 3907 (3.07%) died (1961 patients died of CVD), and 5772 (4.53%) were first hospitalized for CVD.
Table 1 shows the participants baseline characteristics. The average ages of the losartan, ramipril, and conventional groups were 54.1, 54.2, and 53.9 years, of whom 49.8%, 49.7%, and 50.2% were women, respectively. The numbers of patients who used antihypertensive drugs among the 3 groups were 78.7%, 75.4%, and 79.0%, respectively. The number of patients who used antihypertensive drugs in the ramipril group was significant lower than those of the conventional and losartan groups (P = 0.01). The numbers of patients who had a medical history of stroke among the 3 groups were 2.6%, 2.5%, and 2.0%, respectively, and were ranked as losartan group = ramipril group > conventional group (P = 0.04). There was no significant difference between the numbers of patients with CHD (P = 0.74), heart failure (P = 0.66), DM (P = 0.2), dyslipidemia (P = 0.89), and those with obesity (P = 0.79) among the 3 groups.
Incidence and Risk of ESRD
The incidence of ESRD in the losartan, ramipril, and conventional groups was 9.01, 9.03, and 9.18 per 1000 person-years, respectively. The risk of reaching ESRD for patients in the former 2 groups was significantly lower than that in the conventional group. In the losartan (HR: 0.908; 95% confidence interval [CI]: 0.802–0.975; P = 0.01) and ramipril (HR: 0.924; 95% CI: 0.811–0.964; P = 0.02) groups, the risk of reaching ESRD were reduced 9.2% and 7.6% (Table 2), respectively.
All-Cause and Cardiovascular-Cause Mortality
In the losartan, ramipril, and conventional groups, the all-cause mortalities were 4.98, 4.96, and 5.20 per 1000 person-years, respectively. The risks of death in the losartan (HR: 0.754; 95% CI: 0.579–0.901; P < 0.001) and ramipril (HR: 0.431; 95% CI: 0.312–0.655; P < 0.001) groups were significantly lower than that in the conventional group. Losartan and ramipril reduced the risk of all-cause mortality by 24.6% and 56.9%, respectively. The cardiovascular mortalities in the above 3 groups were 2.39, 2.58, and 2.61 per 1000 person-years, respectively. The cardiovascular mortality in the losartan group was significantly lower than that in the conventional group (HR: 0.876; 95% CI: 0.614–0.972, P = 0.03). However, there were slightly different in the risks of cardiovascular mortality between the ramipril and conventional groups was observed (HR: 0.925; 95% CI: 0.801–0.998; P = 0.04).
Incidence of First Hospitalization Due to CVD
The incidences of first hospitalization due to CVD were 7.56/1000 person-years in the losartan group and 7.47/1000 person-years in the ramipril group and were significantly lower than that in the conventional group (7.68/1000 person-years) (losartan group: HR: 0.640, 95% CI: 0.375–0.899, P = 0.01; ramipril group: HR: 0.753, 95% CI: 0.652–0.971, P < 0.001). The risk reduction of first hospitalization due to CVD for patients in the losartan and ramipril groups was 36.0% and 24.7%, respectively.
Average Time to Reach Endpoints
The average times for the patients in the losartan, ramipril, and conventional groups to reach each endpoint are listed in Table 3. The average years to reach ESRD, all-cause mortality, and cardiovascular mortality were 4.9 ± 3.5, 5.0 ± 3.7, and 4.9 ± 3.0 years, respectively, in the losartan group, and 4.9 ± 3.1, 5.1 ± 3.0, and 5.0 ± 3.1 years, respectively, in the ramipril group. No significant difference was observed when the former 2 groups were compared with the conventional group with 4.9 ± 3.2, 5.0 ± 3.6, and 4.9 ± 3.4 years, respectively, for each endpoint.
During the 5.9-year average follow-up period, we discovered the significant association of losartan and ramipril therapy yielded better kidney protection for patients with CKD, compared with conventional antihypertensive drugs. The reductions in ESRD risk by losartan and ramipril were 9.2% and 7.6%, respectively. The reductions of all-cause mortalities for patients in the losartan and ramipril groups were 24.6% and 56.9%, respectively. The risk of first hospitalization due to CVD was also reduced by 36.0% and 24.7%, respectively. The decreased risk of these endpoints for CKD patients provided further evidence for the better prognosis yielded by losartan and ramipril treatments compared with conventional antihypertensive medicines. The risk of cardiovascular mortality decreased by 12.4% in the losartan group-a value that was significantly lower than that in the conventional group. However, there were slightly significant difference was observed between the ramipril and conventional groups. In addition, the average periods for patients to reach the endpoints among the 3 groups did not significantly differ.
Multiple kidney and cardiovascular clinical trials have been limited by a lack of Asian patient enrollment,7,10,18 the under-representation of Asian patients,19–22 a combination of multiple endpoints,9–12,14,15 or a short follow-up period.15 For example, Asians in the VALUE trial,20 Val-HeFT trial,21 and LIFE trial22 were made up of only 3.5%, 2.8%, and 0.9%, respectively, of the total subjects. In addition, none of these trials included Taiwanese subjects. Although some recent studies have included Taiwanese patients as study subjects, the subjects were patients with stage 5 CKD23 or patients receiving kidney replacement therapy.24,25 The follow-up periods in these studies were too short as well. By contrast, the present investigation included nationally representative samples and covered CKD patients at all stages; moreover, this study, with an average follow-up of 5.9 years, was long enough to evaluate the association of losartan and ramipril therapy with kidney and cardiovascular outcomes in hypertensive patients with CKD.
The risk of each endpoint was analyzed using Cox's proportional hazard regression model. The all-cause mortality in the ramipril group was significantly lower than that in the conventional group-a result that differed from that in the Left Ventricular Dysfunction Prevention study.26 However, in our study, the risk of cardiovascular mortality was shown to be slightly lower than that in conventional group, which was consistent with the results from the Heart Outcomes Prevention Evaluation (HOPE) study18 and the ADVANCE trial.27 Significantly reduced risks in endpoints such as ESRD, all-cause mortality, and first hospitalization due to CVD were observed in this study, indicating the explicit association of ramipril therapy on the prognosis of CKD patients.
In this investigation, the risk of all-cause mortality in the ramipril group differed from that in the Left Ventricular Dysfunction Prevention study.26 This difference might be due to the exclusion of patients with impaired kidney function, the inclusion of patients with advanced ages (54.2 vs 59.1 years), and more patients with severe clinical conditions in the latter study. Although the risk of cardiovascular death in patients was consistent with the results from that in the HOPE study18 and the ADVANCE trial,27 the slightly lower risk of cardiovascular mortality (P = 0.04) than that in conventional group might be due to the older age (54.2 vs 66.0 years) of the subjects and more patients with coronary artery disease and stroke in their studies. The ESRD risk reduction in the ramipril group was consistent with the findings by Wright et al,10 Hou et al,14 and Hsu et al.23 However, our records revealed a relatively lower risk than in previous studies,23 possibly because those studies included CKD patients at stage 3 or more advanced stages.
Our study confirmed that losartan treatment in combination with conventional antihypertensive drugs as needed for patients with CKD achieves remarkable cardiovascular and kidney protective functions. The risks of endpoints, including ESRD, all-cause mortality, cardiovascular mortality, and first hospitalization due to CVD, were significantly reduced compared with those of the conventional group. The significant association of losartan therapy on patient prognoses was observed in our study. However, many of these patients had already received medications such as diuretics, direct vasodilators, and beta-blockers. Likewise, patients who received calcium channel antagonists did not show an altered losartan effect, although a few studies suggested otherwise in terms of the effect of calcium channel antagonists in protecting cardiovascular and kidney functions.28,29 From the analysis of endpoint risks, patients in the losartan group showed a significantly lower ESRD risk than did the conventional group, which was in agreement with several previous studies.6–14 The all-cause mortality of patients in this group was significantly lower than that of the conventional group but different from the results in the Jikei Heart study,15 VALUE trial,20 Val-HeFT trial,21 LIFE trial,22 and Barry study.9 The cause might be the older research subjects included in their studies (54.1 vs over 60.0 years). The risk of cardiovascular mortality in this study also differed from the results of the Jikei Heart study, VALUE trial, and LIFE trial. All of these results suggest that although observable prognosis association were observed for losartan and ramipril in patients with hypertension and CKD, these outcomes should not be over-interpreted.
The periods for the patients to reach various endpoints showed no differences among the 3 groups, possibly due to the application of clinical outcomes instead of biochemical laboratory data as evaluation criteria. The clinical outcomes of patients (including ESRD, mortality, and first hospitalization due to CVD) usually required a relatively long period after receiving medication to be observable. By contrast, biochemical laboratory data could reveal variations within a relatively short time. In addition, the results from this study suggested that losartan and ramipril exhibit distinct association on the prognosis of CKD patients. However, several investigations have also suggested that ACEi/ARB administration increases the risk of hyperkalemia in some patients,8,10,12,14,23 resulting in the switching to other drugs and affecting the endpoint of these patients. Therefore, the periods for the patients to reach various endpoints did not differ among the 3 groups.
This study has several strengths. First, it includes a nationally representative sample. The large sample size allowed us to evaluate the association of losartan and ramipril therapy for the specific endpoint. Second, in contrast with previous studies that did not cover CKD patients at all stages,7,8,10–12,14,23 we not only included the complete profile of various clinical conditions but also tracked the changes in potential comorbidities developed with time. Third, this study could confirm the results of all study subjects. By contrast, previous studies have included subjects who withdrew or were lost to follow-up, thus failing to follow their endpoints.7,8,10,12,14 However, this study also exhibited a few limitations. First, because coding of disease and prescription for medical conditions are related to physician practice patterns (eg, perhaps the physicians’ prescription of ACEi or ARB were more competent, conscientious, and global in their management of patients’ health issues), which are known to vary substantially, and data on physician practice patterns were unavailable for analysis in this study, we cannot rule out that patterns.30 Second, the database analysis in this study was claim based, and the definition of kidney disease used diagnostic codes rather than a systemic check for kidney impairment. Because laboratory data (such as serum creatinine, urine protein, etc.) and physical examination information (such as blood pressure, etc.) were not available in the NHIRD, we could not confirm the CKD stage in these patients or further analyze the different prognostic effects of losartan and ramipril on patients with different severities of CKD. However, this limitation did not prevent us from confirming the study subjects because, in Taiwan, the diagnosis of kidney disease was based on the estimated glomerular filtration rate. Third, clinical conditions were defined based on diagnostic codes, and misclassification was possible. However, the misclassification might have been random; thus, it would be more likely to underestimate rather than over-estimate the association. Fourth, we could confirm the time when different diseases were diagnosed but not the time of onset. This issue can be minimized as much as possible by optimizing the research design.
In summary, the results from this study indicated that losartan and ramipril exhibit significant association with the prognosis of patients with hypertension and CKD, and was first to disclose that the mean time to reach each endpoint for patients in the losartan, ramipril, or conventional group was not significantly different. Therefore, the association of losartan and ramipril therapy with the prognosis of CKD patients should not be over interpreted. In addition, we held reservation on the approach to combine multiple endpoints in evaluating the clinical effect of ACEi and ARB.
The authors thank an anonymous reviewer for critical reading of the manuscript.
1. Schoolwerth AC, Engelgau MM, Hostetter TH, et al. Chronic kidney disease: a public health problem that needs a public health action plan. Prev Chronic Dis
2. Kuo HW, Tsai SS, Tiao MM, et al. Epidemiological features of CKD in Taiwan. Am J Kidney Dis
3. Lysaght MJ. Maintenance dialysis population dynamics: current trends and long-term implications. J Am Soc Nephrol
2002; 13 (Suppl 1):S37–S40.
4. US Renal Data System. USRDS 2012 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States
. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2012.
5. Levey AS, Atkins R, Coresh J, et al. Chronic kidney disease as a global public health problem: approaches and initiatives—a position statement from Kidney Disease Improving Global Outcomes. Kidney Int
6. Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med
7. The, GISEN., Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet
8. Ruggenenti P, Perna A, Gherardi G, et al. Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Lancet
9. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med
10. Wright JT, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA
11. De Zeeuw D, Remuzzi G, Parving HH, et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation
12. Hou FF, Zhang X, Zhang GH, et al. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med
13. Mann JF, McClellan WM, Kunz R, et al. Progression of renal disease—can we forget about inhibition of the renin–angiotensin system? Nephrol Dial Transplant
14. Hou FF, Xie D, Zhang X, et al. Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency. J Am Soc Nephrol
15. Mochizuki S, Dahlöf B, Shimizu M, et al. Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study. Lancet
17. Chinese Hospital Association. ICD-9-CM English-Chinese Dictionary
. Taipei, Taiwan: Chinese Hospital Association Press; 2000.
18. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med
19. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet
20. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet
21. Cohn JN. Tognoni G for the Valsartan Heart Failure Trial Investigators: a randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med
22. Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet
23. Hsu TW, Liu JS, Hung SC, et al. Renoprotective effect of renin-angiotensin-aldosterone system blockade in patients with predialysis advanced chronic kidney disease, hypertension, and anemia. JAMA Intern Med
24. Hwang SJ, Yang WC, Lin MY, et al. Impact of the clinical conditions at dialysis initiation on mortality in incident haemodialysis patients: a national cohort study in Taiwan. Nephrol Dial Transplant
25. Li PK, Chow KM, Wong TY, et al. Effects of an angiotensin-converting enzyme inhibitor on residual renal function in patients receiving peritoneal dialysis: a randomized, controlled study. Ann Intern Med
26. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med
27. Patel A. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet
28. Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med
29. Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA
30. Winkelmayer WC, Schneeweiss W, Mogun H, et al. Identification of individuals with CKD form Medicare claims data: a validation study. Am J Kidney Dis