Correspondence

The COOPERATE trial: a letter of concern

The understanding of hypertensive chronic kidney disease (CKD) has recently been reshaped by the discovery of risk alleles associated with kidney disease. Recent studies have also changed our understanding of therapeutic targets for blood pressure control in the CKD population. Pharmacological and nonpharmacological hypertension interventions to control progression of CKD continue to evolve.

Soon after the emergence of the renin-angiotensin-aldosterone system (RAAS) blocking treatment as the cornerstone of renoprotective treatment in the prevention and treatment of diabetic and nondiabetic CKD, it was investigated if a higher degree of achievable RAAS blockade by combining more than one compound is feasible and advantageous. Regardless of the benefits from using monotherapy for diabetic kidney disease, there is still much improvement to wish for in terms of kidney prognosis in these populations. A great deal of research has gone into evaluating combinations of the RAAS blocking treatments in different populations and with different drugs and doses. Studies have mostly been short-term and use surrogate endpoints such as albuminuria. Side effects have been well known and expected in terms of increasing potassium levels and hypotension, but to an acceptable extent. With recent disappointing results from major hard endpoint trials using dual RAAS blockade the concept is now under scrutiny. In this review we will discuss the pros and cons of dual RAAS blockade, with facts and findings from smaller studies, endpoint trials, and meta-analyses.

Treatment of chronic kidney disease (CKD) can slow its progression to end-stage renal disease (ESRD). However, the therapies remain limited. Blood pressure control using angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) has the greatest weight of evidence. Glycemic control in diabetes seems likely to retard progression. Several metabolic disturbances of CKD may prove to be useful therapeutic targets but have been insufficiently tested. These include acidosis, hyperphosphatemia, and vitamin D deficiency. Drugs aimed at other potentially damaging systems and processes, including endothelin, fibrosis, oxidation, and advanced glycation end products, are at various stages of development. In addition to the paucity of proven effective therapies, the incomplete application of existing treatments, the education of patients about their disease, and the transition to ESRD care remain major practical barriers to better outcomes.

Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers are considered the standard of care for treatment of cardiovascular disease and chronic kidney disease. Combination therapy with both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers effectively inhibits the renin–angiotensin system as well as potentiates the vasodilatory effects of bradykinin. It has been advocated that this dual blockade approach theoretically should result in improved clinical outcomes in both cardiovascular disease and chronic kidney disease. Clinical trial evidence for the use of combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in cardiovascular disease has provided conflicting results in hypertension, congestive heart failure, and ischemic heart disease. Clinical trial evidence to support combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chronic kidney disease has largely been based on proteinuria reduction as a surrogate marker for clinically meaningful outcomes. Recent large-scale randomized clinical trials have not been able to validate protection in halting progression in chronic kidney disease with a dual blockade approach. This review serves as an appraisal on the clinical evidence of combination angiotensin-converting enzyme inhibition and angiotensin II receptor blockade in both cardiovascular disease and chronic kidney disease.