Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials
BMJ 2013; 347 doi: https://doi.org/10.1136/bmj.f5680 (Published 03 October 2013) Cite this as: BMJ 2013;347:f5680All rapid responses
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Different Strategies to Choose Antihypertensive Drugs?
Wu H-Y, et al reported that compared with placebo, only angiotensin converting enzyme (ACE) inhibitors significantly reduced the doubling of serum creatinine levels and ACE inhibitor plus calcium channel blocker combination therapy had the greatest probability for being the best treatment on reducing mortality. Therefore, they concluded that the renoprotective effects and superiority of using ACE inhibitors in patients with diabetes, supporting the use of ACE inhibitors as the first line antihypertensive agent in patients with diabetes, considering the cost of drugs. Calcium channel blockers might be the preferred treatment in combination with ACE inhibitors if adequate blood pressure control cannot be achieved by ACE inhibitors alone.1
By contrast, another paper reported that compared with placebo, blood pressure lowering regimens reduced the risk of major cardiovascular events by about a sixth per 5 mm Hg reduction in systolic blood pressure in individuals with (hazard ratio 0.83) and without reduced eGFR, with no evidence for any difference in effect. The results were similar irrespective of whether blood pressure was reduced by regimens based on ACE inhibitors, calcium antagonists, or diuretics/β blockers. There was no evidence that the effects of different drug classes on major cardiovascular events varied between patients with different eGFR.2 In summary, blood pressure lowering is an effective strategy for preventing cardiovascular events among people with moderately reduced eGFR, however, there is little evidence to support the preferential choice of particular drug classes for the prevention of cardiovascular events in chronic kidney disease.
In the past time, the goal to treat patients in hypertension was merely to control each numerical number such as blood pressure (BP) level alone, however, nowadays, it changed. The updated guidelines target reducing overall cardiovascular risks3,4. Hypertension is both associated with endothelial dysfunction and insulin resistance and their coexistence has vicious cycle associated with an increased incidence of cardiovascular events. In this regard, chronic inflammation and oxidative stress play crucial roles in endothelial dysfunction, insulin resistance, and atherosclerosis.5 Chronic inflammation is a pathogenic feature of atherosclerosis and cardiovascular disease mediated by various substances including angiotensin II, proinflammatory cytokines, and free fatty acids. Moreover, additional mechanisms contributing independently to both insulin resistance and endothelial dysfunction include glucotoxicity, lipotoxicity, and inflammation together with oxidative stress.6,7 Controlling a variety of risk factors causing inflammation and oxidative stress with renin-angiotensin-aldosterone system blockade therapy may simultaneously address multiple mechanisms underlying the pathogenesis of atherosclerosis. This emerging therapeutic paradigm for slowing progression of atherosclerosis has advantages.8 Therefore, new guidelines recommend to use ACE inhibitors to slow progression of renal damage and reduce cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus and kidney disease.3,4
So, this view is not consistent to the current paper2. Of course, blood pressure lowering is an effective strategy for preventing cardiovascular events among people regardless of kidney function. Therefore, 2013 European and American guidelines recommend ACE inhibitors in combination with calcium channel blockers as the preferred treatment because of a prompter response in a larger number of patients (potentially beneficial in high-risk patients), a greater probability of achieving the target blood pressure in patients with higher blood pressure values, and a lower probability of discouraging patient adherence with many treatment changes.3,4
Funding: None, Disclosures: None
REFERENCES
1. Wu HY, Huang JW, Lin HJ, Liao WC, Peng YS, Hung KY, et al. Comparative effectiveness of renin-angiotensin system blockers and other antihypertensive drugs in patients with diabetes: systematic review and bayesian network meta-analysis. BMJ 2013;347:f6008.
2. Blood Pressure Lowering Treatment Trialists' Collaboration. Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials. BMJ 2013;347:f5680.
3. Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M, et al; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013;31:1281-357.
4. Go AS, Bauman M, Coleman King SM, Fonarow GC, Lawrence W, Williams KA, et al. AHA/ACC/CDC Science Advisory: An Effective Approach to High Blood Pressure Control A Science Advisory From the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. J Am Coll Cardiol 2013 Nov 12. doi:pii: S0735-1097(13)06077-4. 10.1016/j.jacc.2013.11.007.
5. Koh KK, Oh PC, Quon MJ. Does reversal of oxidative stress and inflammation provide vascular protection? Cardiovasc Res 2009;81:649-59.
6. Han SH, Quon MJ, Koh KK. Reciprocal relationships between abnormal metabolic parameters and endothelial dysfunction. Curr Op Lipidol 2007;18:58-65.
7. Muniyappa R, Montagnani M, Koh KK, Quon MJ. Cardiovascular actions of insulin.
Endocr Rev 2007;28:463-91.
8. Lee H-Y, Sakuma I, Ihm S-H, Goh C-W, Koh KK. Statins and renin-angiotensin system inhibitor combination treatment to prevent cardiovascular disease. Cir J 2014 (in press)
Competing interests: No competing interests
Do Black Patients with Chronic Kidney Disease Benefit Equally from All Blood Pressure Agents?
Joseph A. Ladapo, MD, PhD1 Gbenga Ogedegbe, MD, MS, MPH1
1Department of Population Health, New York University School of Medicine, New York, NY
The Blood Pressure Lowering Treatment Trialists’ Collaboration performed an important analysis of the impact of various antihypertensive agents on cardiovascular outcomes (stroke, myocardial infarction, heart failure, and cardiovascular death) in patients with and without chronic kidney disease.(1) We commend them for their rigorous and insightful analysis, but believe it is important to draw a cautionary note about their conclusion that, “[t]here is little evidence to support the preferential choice of particular drug classes for the prevention of cardiovascular events in people with chronic kidney disease.” This may be true for individuals of all racial/ethnic groups, and results from the African American Study of Kidney Disease and Hypertension (AASK)(2) do not conflict with this conclusion, but we know from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)(3) and other trials enrolling black patients(4) that the choice of antihypertensive agents, at least when a single agent is used, does matter in black patients. For example: in ALLHAT, black patients treated with lisinopril rather than chlorthalidone were more likely to experience stroke (P < 0.001) and combined cardiovascular events (comprising coronary heart disease death, nonfatal myocardial infarction, stroke, angina, coronary revascularization, heart failure, and peripheral vascular disease; P < 0.001); these findings were absent in non-black patients and persisted after time-dependent adjustment for blood pressure (albeit a method less robust than the Collaboration’s weighting approach but more clinically relevant). Moreover, the risk of incremental harms from angiotensin-converting enzyme (ACE) inhibitors is also supported by a systematic review of randomized trials of antihypertensive drug therapy in black patients.(4)
Because hypertension-related morbidity and mortality is so disproportionately pronounced in black patients compared to other racial/ethnic groups,(5) the existing evidence leads us to believe that a subgroup analysis comparing black to non-black patients in the Collaboration’s study of chronic kidney disease would be appropriate and should, perhaps, be the rule rather than the exception in studies of hypertension whenever feasible. It appears that the Collaboration has patient-level data from at least some of the trials; using these data to robustly assess whether their overall conclusion about drug class agnosticism is equally applicable to blacks and non-blacks could be of substantial value to clinicians--and would be a generous service to the millions of black patients with hypertension and chronic kidney disease.
References
1. Ninomiya T, Perkovic V, Turnbull F, Neal B, Barzi F, Cass A, et al. Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials. BMJ. 2013;347:f5680.
2. Wright JT, Jr., Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288(19):2421-31.
3. Wright JT, Jr., Dunn JK, Cutler JA, Davis BR, Cushman WC, Ford CE, et al. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA. 2005;293(13):1595-608.
4. Brewster LM, van Montfrans GA, Kleijnen J. Systematic review: antihypertensive drug therapy in black patients. Annals of internal medicine. 2004;141(8):614-27.
5. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation. 2010;121(7):e46-e215.
Competing interests: No competing interests
Dear Editor,
In the "Methods" the authors stated that "Main outcome measures (were) Major cardiovascular events (stroke, myocardial infarction, heart failure, or cardiovascular death) in composite and individually and all cause death."
But they did not provide any data on the all cause death rate in the article. It is difficult to imagine that authors and editors do not consider the total mortality as a clinically important outcome.
From the Appendix tables we see that:
1) authors know that there is a kind of bias called 'selective reporting';
2) it looks like there is a difference in total mortality between one treatment and placebo.
Why was this not reported/commented on?
Would the authors fill the omission?
Competing interests: No competing interests
One of the consequences of hypertension is end-organ damage, and in the context of this current review – kidney disease, and subsequently, end stage renal failure. One of the consequences of kidney disease is that it can potentiate and worsen hypertension. Normal blood pressure (BP) is <120/80, whilst for pre-hypertension, the range is 120 – 139/80 - 89. For stage 1 hypertension, the range is 140 – 159/90 – 99 and for stage 2, ≥160/≥100.
To this end, Perkovic performed a meta-analysis of randomised trials that looked at BP lowering drugs versus placebo or with each other that compared different BP targets. The analysis also included patients with reduced estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2. The main outcome measures were cardiovascular events such as myocardial infarction, stroke, heart failure or cardiovascular death in composite and individual, and all-cause mortality. The results obtained demonstrated the significant impact of lowering BP, specifically, BP lowering regimes lowered cardiovascular events by about a sixth per 5 mm Hg reduction in BP in individuals with (hazard ratio = 0.83, CI: 0.76 – 0.90) and without (hazard ratio = 0.83, CI:0.79 – 0.88) reduced eGFR. The results were similar irrespective of the agent (angiotension converting enzyme inhibitors, calcium antagonists, diuretics/β-blockers) used to reduce BP.
What is the implication of this finding on clinical practice, with respect to management of patients with hypertension but who do not have any target organ damage and other co-morbidities? It is not going to change current clinical practice whose goal is to bring the hypertensive patient’s BP into normotensive range (target depends on other co-morbidities). Perkovic’s analysis involved trials that explored the use of medications to lower BP, but realistically in clinically practice, when the patient is first diagnosed with hypertension, the initial approach is to trial the latter on lifestyle modifications, i.e. dietary, smoking and alcohol avoidance/cessation, physical activity, weight reduction and stress management. [1] For instance, in a trial to evaluate the use of Dietary Approaches to Stop Hypertension (DASH) diet, it was found that the recommended dietary approach significantly lowered systolic BP in comparison with control diet (-11.2 mm Hg, CI: -6.1 to- 16.2). [2] Failure of lifestyle modification to lower BP to normotensive range will lead to the consideration of pharmacotherapy.
Therefore, it will be interesting to ask this question – for every 5 mm Hg reduction in systolic BP by lifestyle modification approaches, by how much will it impact the relative risk of cardiovascular events? Secondly, it will be more informative for Perkovic to sub-divide the patients into differing stages of hypertension, i.e. what is the impact on cardiovascular events in stage 2 hypertensive patients who managed to reduce their BP by 5 mm Hg versus that of stage 1 patients for instance?
Research is also beginning to demonstrate that sub-clinical factors can be predictor of risk of cardiovascular events. In the Heinz Nixdorf Recall Study, which was aimed at improving prediction of cardiovascular events by integrating new imaging and non-imaging modalities in risk assessment, it was found that subclinical atherosclerosis predicted cardiovascular risk in specific stages of hypertension. The investigators evaluated coronary artery calcification (CAC) in patients using imaging modalities and found that the risk of cardiovascular events in hypertensive and pre-hypertensive subjects depended on the degree of CAC. [3]
In patients with chronic kidney disease (CKD) and hypertension, the situation is not as simplistic. Mahmoodi and colleagues performed a meta-analysis of studies selected according to the CKD Prognosis Consortium criteria, and subsequently published in the Lancet. They found that hypertensive patients have a higher risk of mortality with regards to all-cause mortality in eGFR range of > 55 mL/min/1.73 m2 and higher cardiovascular mortality in eGFR > 45 mL/min/1.73 m2. However, interestingly, the authors found a steeper relative risk gradient within the eGFR range of 45 – 75 mL/min/1.73 m2 in non-hypertensive patients in comparison with their hypertensive peers, which led to the same mortality risk for both groups at lower eGFR. At 45 mL/min/1.73 m2, the adjusted hazard ratio (HR) for all-cause mortality was 1.77 (CI:1.57 – 1.99) for non-hypertensive patients versus 1.24 for (1.11 – 1.39) for those with hypertension (P for overall interaction = 0.0003). And when they examined the effects of albumin-creatinine ratio (ACR) of 300 mg/g, HR was 2.30 (1.98 – 2.68) in individuals without hypertension vs 2.08 (1.84 – 2.35) in those with hypertension (p for overall interaction = 0.019). Taken together, these results implied that low eGFR and high ACR demonstrated dose-dependent association with all-cause and cardiovascular mortality in individuals with and without hypertension. In fact, rather surprisingly, the mortality outcomes were stronger in individuals without hypertension as opposed to those with hypertension. [4]
Thus, it seems that besides the traditional risks factors, there is another one that accounts for the high frequency of cardiovascular disease in CKD patients. Vascular calcification (VC) including that of the coronary arteries, which was covered earlier, is a major problem in the setting of CKD, and represents a distinct pathogenic process resulting in cardiovascular complications. The causes are hyperphosphatemia and elevated calcium phosphate products in these patients. In fact, the extent and histoanatomic type of vascular calcification are predictors of subsequent mortality.[5] Therefore, the management of hyperphosphatemia besides BP impacts on the extent of mortality and can be a confounding factor if the goal is just to study BP lowering effects alone.
Hence, in terms of managing hypertensive CKD patients, lowering BP is important as Perkovic’s study has demonstrated but the current principles of management do not change. This includes monitoring of BP, eGFR and for proteinuria. Besides the control of BP, blood sugars in the setting of diabetes and other lifestyle factors, hyperphosphatemia control is another important aspect, which can be achieved by dietary restriction or/and together with phosphate binder drugs.
1.Gupta R, Guptha S. Strategies for initial management of hypertension. Indian J Med Res. 2010 Nov;132:531-542.
2. Moore TJ, Conlin PR, Ard J, Svetkey LP. DASH (Dietary Approaches to Stop Hypertension) diet is effective treatment for stage 1 isolated systolic hypertension. Hypertension. 2001 Aug;38(2):155-158
3. Erbel R, Lehmann N, Möhlenkamp S, Churzidse S, Bauer M, Kälsch H, Schmermund A, Moebus S, Stang A, Roggenbuck U, Bröcker-Preuss M, Dragano N, Weimar C, Siegrist J,Jöckel KH; Heinz Nixdorf Recall Study Investigators. Subclinical coronary atherosclerosis predicts cardiovascular risk in different stages of hypertension: result of the Heinz Nixdorf Recall Study. Hypertension. 2012 Jan;59(1):44-53.
4. Mahmoodi BK, Matsushita K, Woodward M, Blankestijn PJ, Cirillo M, Ohkubo T, Rossing P, Sarnak MJ, Stengel B, Yamagishi K, Yamashita K, Zhang L, Coresh J, de Jong PE,Astor BC; Chronic Kidney Disease Prognosis Consortium. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis. Lancet. 2012 Nov 10;380(9854):1649-1661.
5. Mizobuchi M, Towler D, Slatopolsky E. Vascular calcification: the killer of patients with chronic kidney disease. J Am Soc Nephrol. 2009 Jul;20(7):1453-1464.
Competing interests: No competing interests
Dear Blood Pressure Lowering Treatment Trialists Collaboration:
I have read with interest your well done and powerful meta-analysis, but I could not find more detailed information about major cardiovascular events reductions in three populations, with peculiarities, but also with high cardiovascular risk, beyond eGFR below 60 ml/min: The diabetics, the elderly (≥65 years), and for the variable of body mass index.
For the diabetics there are lots of controversies regarding optimal blood pressure levels or targets(1,2), for the elderly a U shaped relationship with many, if not all, traditional cardiovascular risk factors like Hypertension(3), and the benefits of the obesity paradox, namely for those over 50 to 60 years, well documented in many, if not all, major studies(4). It would be great if you could provide to us more information about these three important cardiovascular issues and common companions of Hypertension?
And Finally, in this huge population how much evidence was found of Harms induced by overtreatment of Hypertension?(5)
REFERENCES:
1. Zhao W, Katzmarzik PT, Horswell R, Wang Y et al. Aggressive Blood Pressure Control Increases Coronary Heart Disease Risk Among Diabetic Patients. Diabetes Care. Published Ahead of Print online. May 20 2013. DOI : 10.2337/dc 13-0189
2. Zhao W, Katzmarzik PT, Horswell R, Wang Y et al. Blood Pressure and Stroke Risk among Diabetic Patients. J Clin Endocrin Met. First published ahead of print May 28, 2013 as DOI : 10.1210/jc.2013-1757.
3. Visher UM, Safar ME, Safar H, et al. Cardiometabolic determinants of mortality in a geriatric population : Is there a « reverse metabolic syndrome »? Diabetes Metab. 2009 ; 35 : 108-14.
4. Flegal KM, Kit BK, Orpana H, Graubard BL. Association of All-Cause Mortality With Overweight and Obesity Using Standard Body Mass Index Categories. A Systematic Review and Meta-Analysis. JAMA January 2 2013; 309: 71-82.
5. Heath I. Waste and Harm in the Treatment of Mild Hypertension. JAMA Intern Med. Published online May 13 3013.
Competing interests: No competing interests
Re: Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials
Dear Sir,
We would like to thanks Drs Lapado and Ogedegbe for their important comments in response to our paper. They rightly point out data suggesting that individuals from different ethnic groups may respond differently to BP lowering therapy, as demonstrated for African Americans compared to Americans of other backgrounds. This is an important question for which there is a substantial amount of data from individual trials, however there is no data to our knowledge that suggests ethnic differences might be further modified by kidney function.
The Blood Pressure Lowering Treatment Trialists' Collaboration is a prospectively planned series of meta-analyses, with prespecified hypotheses, outcome and analysis plans. The protocol has prespecified subgroup analyses with tests of interaction performed to assess the association of any treatment differences with several patient characteristics-namely-age, sex, diabetes status, and baseline blood pressures levels and kidney function level. While ethnicity was not included in the original prespecified secondary analyses, we will explore opportunities to undertake these analyses with members of the collaboration across all levels of kidney function.
Competing interests: No competing interests