Introduction
Biological links between the RAAS and lung cancer
RAAS blockade and risk of lung cancer
Meta-analyses
Population-based studies
References | Population | Number of patients | Time period Follow-up | Inclusion criteria | RAAS blocker | Effect |
---|---|---|---|---|---|---|
Lever et al. (1998) | Registrar General Scotland database East of Scotland Cancer Registry | 5207 | 1980–1995 follow-up 6,6 (SD 4.5) years | Hypertension treated in the clinic | ACEIs, all cancers | Reduced risk |
ACEI, Smoking related cancers | Reduced risk | |||||
Other antihypertensive drugs, all cancers | No effect | |||||
Friis et al. (2001) | Prescription Database of North Jutland County and the Danish Cancer Registry | 17,897 | 1989–1995 follow-up 3.7 years (range 0–8) | Prescriptions of ACEI | ACEI, lung cancer, all cancers | No effect |
ACEI vs beta-blockers or calcium channel blockers, all cancers, lung cancer | No effect | |||||
Chang et al. (2011) | Taiwan National Health Insurance claims database | 21,750 | 2000 median follow up 7.4 years | New diabetic patients | ARBs: all, all cancers | No effect |
ARBs: Losartan, all cancers | Reduced risk | |||||
ARBs: Candesartan and telmisartan, all cancers | Increased risk | |||||
Huang et al. (2011) | Taiwan National Health Insurance Research Database | 109,002 40,124 ARB users 68,878 controls | 1998–2006 Mean follow-up 5.7 (SD 2.6) years | New hypertensive patients | ARB vs controls, all cancers | Reduced risk |
Pasternak et al. (2011) | Danish registries on filled drug prescription | 107,466 ARB 209,692 ACEI | 1998–2006 Follow-up ARB users 140,562 person-years ACEI users 163,617 person-years | New ARB/ACEI users | ARB/ACEI combined, all cancers, lung cancer | No effect |
Azoulay et al. (2012) | UK General Practice Research Database | 1,165,781 | 1995–2010 Mean follow-up 6.4 (SD 3.9) years | New diagnosis of lung, colorectal, breast and prostate cancer | ARBs vs diuretics/ß-blockers, all cancers, lung cancer | No effect |
ACEIs vs diuretics/ß-blockers, lung cancer | Increased risk | |||||
Bhaskaran et al. (2012) | UK General Practice Research Database | 377,649 340,589 ACEI 37,060 ARB | 1995–2010 median follow-up 4.6 years | New ACEI or ARB users with at least one year of initial treatment | Combined ACEI/ARB, lung cancer | Reduced risk |
Combined ACEI/ARB, all cancers | No effect | |||||
Rao et al. (2013) | Department of Veterans Affairs electronic medical record system and registries | 1,229,902 | 1999–2010 mean follow-up 4.5 (SD 2.1) years | New ARB dispensation Controls = randomly identified patients in 1:15 ratio | ARB vs controls, lung cancer | Small risk reduction |
Chiang et al. (2014) | Taiwan National Health Insurance Research Database | 6,960 ARB 4,988 ACEI 143,887 non ACEI/ARB | 2000–2008 Mean follow-up ACEI 2.36 (SD1.81) ARB 2.38 (SD1.77) years | Essential hypertension no COPD no cancer | ARB vs control, all cancers | Reduced risk |
ACEI vs control, all cancers | Reduced risk | |||||
Gokhale et al. (2016) | 20% sample of the Medicare claims | 108,116 ARB 342,611 ACEI | 2007–2012 median follow-up 0.7 years | New ARB/ACEI users | ARBs, lung cancer | No effect |
ACEIs, lung cancer | No effect | |||||
Tascilar et al. (2016) | UK Clinical Practice Research Datalink | 60,109 | 2000–2008 mean follow-up 3.9 (SD 2.2) years | New ARB users | Telmisartan compared to other ARBs, lung cancer, all cancers | No effect |
Hicks et al. (2018) | United Kingdom Clinical Practice Research Datalink | 992,061 335,135 ACEI 29,008 ARB 101,637 both ACEIs and ARBs | 1995–2015 mean follow-up 6.4 (SD 4.7) years | New antihypertensive drug users | ACEI vs ARB | Increased risk |
Cumulative duration of ACEI use | Increasing risk with longer duration (≤ 5; 5–10; > 10 Years) | |||||
Lin et al. (2020) | National Health Insurance Research Database (NHIRD) and Taiwan Air Quality Monitoring Database (TAQMD) | 22,384 ACEI 22,384 ARB | 2000–2012 mean follow-up: 6.33 ± 3.52 years ARB 6.12 ± 3.47 years ACEI | New ARB/ACEI users No known history of cancer | ACEIs vs ARBs, lung cancer | Increased risk |
Critical appraisal
Statement of regulatory agencies
RAAS blockade and clinical outcome of lung cancer patients
References | Design | Number of patients | Time period | Inclusion criteria | Results | |
---|---|---|---|---|---|---|
Wilop et al. (2009) | Retrospective analysis | 287 | 1996–2007 | Long-term medication with ACEI or ARB advanced NSCLC (Stage IIb or IV) undergoing first-line platinum-based chemotherapy | 52 ACEI/ARB (43/9) vs 235 non ACEI/ARB | OS 11.7 vs. 8.6 months, HR 0.56, p = 0.03 |
Aydiner et al. (2015) | Retrospective analysis | 37 ACEI/ARB 80 non ACEI/ARB Matched 1:2 | 2003–2011 | NSCLC stage IV Chemotherapy or Erlotinib | ACEI/ARB overall | HR 0.99 (95%CI 0.49–2.00) p = 0.98 |
ACEI/ARB + Erlotinib | HR 0.37 (95%CI 0.17–0,76) p = 0.008 | |||||
Miao et al. (2016) | Retrospective analysis | 228 advanced NCCLC 73 early-stage disease | 2000–2014 | Histologically confirmed advanced NCCLC (stage IIIb or IV) or early-stage disease (stage I-IIIa) and platinum-based chemotherapy | 112 TKI ± Chemotherapy 18 ACEI/ARB vs 94 non-ACEI/ARB | PFS 11.2 vs 8.0 months (p = 0.044) OS not significant |
228 advanced NSCLC 38 ACEI/ARB vs 190 non-ACEI/ARB | PFS 7.3 vs 5.2 months (p = 0.036) OS not significant | |||||
73 early stage /surgery 14 ACEI/ARB vs 59 non-ACEI/ARB | PFS not significant OS not significant | |||||
Menter et al. (2017) | Retrospective analysis | 1813 patients 273 of 1,465 CP had ACEI/ARB 78 of 348 had CBP + ACEI/ARB | 2005–2011 | patients with advanced NSCLC concomitant RAAS blocker treatment during 1L CP without or with bevacizumab (CPB) | CP with vs. without concomitant ACEI/ARB | Median OS 12.9 vs 8.4 months (crude HR 0.72, 95% CI 0.63–0.84) statistically significant |
CPB with vs. without concomitant ACEI/ARB | Median OS was 14.9 vs 11.9 months (crude HR 0.77, 95% CI 0.57–1.02) not statistically significant | |||||
Wang et al. (2017) | meta-analysis | 9 studies 29,156 patients | All studies until 02/2017 | Lung cancer ARBs/ACEIs usage | Lung cancer patients | OS: pooled HR 0.86 (95% CI: 0.76–0.98, p = 0.022) PFS: no demonstrable impact |
NSCLC vs all types of lung cancer | HR 0.78 (95% CI, 0.65–0.93) vs HR 0.96 (95% CI, 0.81–1.13) p = 0.005 | |||||
Advanced clinical stage IIIb to IV | HR 0.77 (95% CI, 0.64–0.92) | |||||
ACEIs usage group vs ARBs usage group | OS: pooled HR 0.83 (95% CI, 0.53–1.30) and 0.95 (95% CI, 0.74–1.22) | |||||
Wei et al. (2019) | Retrospective cohort | 678 Chinese patients ACEI n = 97, ARB n = 117 non-ACEI/ARB n = 461 | 2016–2018 | Patients using anti-hypertensive drugs at least six months before the first diagnosis of lung cancer | Chemotherapy (n = 117) 38 ACEI/ARB (32.5%) vs 79 non-ACEI/ARB (67.5%) | PFS 10.7 (ACEI/ARB) vs. 6.7 months (non-ACEI/ARB), p = 0.040 OS no significant difference |
ACEI (n = 20) vs non-ACEI/ARB (n = 76) | PFS (12.9 vs 6.4, p = 0.014) | |||||
ARB (n = 18) vs non-ACEI/ARB (n = 76) | PFS (6.7 vs 6.4, p = 0.581) |