ACE Inhibitors: Initiation, Titration and Creatinine Monitoring

Definition and Pathophysiology

Angiotensin-converting enzyme inhibitors (ACE inhibitors) constitute a cornerstone in the management of cardiovascular disease, heart failure, and chronic kidney disease (CKD). These agents interfere with the renin-angiotensin-aldosterone system (RAAS) by inhibiting the enzyme responsible for the conversion of angiotensin I to angiotensin II. By abrogating the effects of angiotensin II, ACE inhibitors stabilize left ventricular remodeling, improve patient symptoms, prevent hospitalization, and prolong life.

Furthermore, because ACE inhibitors also inhibit kininase II, they may lead to the upregulation of bradykinin, which further enhances the effects of angiotensin suppression. In the context of chronic kidney disease, ACE inhibitors slow the rate of decline of kidney function in a manner that extends beyond the reduction of systemic arterial pressure. This renoprotective effect involves a reduction in intraglomerular hyperfiltration and hypertension by disproportionately reducing glomerular efferent arteriolar vasoconstriction.

Clinical Presentation and Symptoms

The source material does not provide specific information on the clinical presentation and symptoms of the underlying conditions for which ACE inhibitors are prescribed.

Evaluation and Physical Examination

Prior to initiating an ACE inhibitor, it is essential to evaluate the patient's volume status. Because fluid retention can attenuate the effects of ACE inhibitors, it is preferable to optimize the dose of diuretic first. However, clinicians may need to reduce the dose of diuretic during the initiation of an ACE inhibitor to prevent symptomatic hypotension.

Diagnostics

The source material does not cover specific diagnostic modalities such as ECG, imaging, or electrophysiology in relation to ACE inhibitor therapy.

Biomarkers and Laboratory Findings

Monitoring renal function and potassium is a critical component of ACE inhibitor therapy. Blood pressure (including postural changes), renal function, and potassium should be evaluated within 1 to 2 weeks after initiation of ACE inhibitors, especially in patients with preexisting azotemia, hypotension, hyponatremia, diabetes mellitus, or in those taking potassium supplements.

When managing albuminuria or CKD, the serum creatinine and potassium should be monitored while increasing to the maximum tolerated dose. A rise in the serum creatinine up to 30% is considered acceptable. In the setting of acute heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP) values, potassium concentrations, and estimated glomerular filtration rate (eGFR) should be assessed during follow-up visits after discharge.

Treatment and Management

Heart Failure with Reduced Ejection Fraction (HFrEF)

There is overwhelming evidence that ACE inhibitors should be used in symptomatic and asymptomatic patients with a reduced ejection fraction (EF <40%), representing a class I indication. ACE inhibitors have consistently shown benefit for patients with symptomatic LV dysfunction, and all placebo-controlled chronic HFrEF trials using neurohormonal antagonists have demonstrated a reduction in mortality. The absolute benefit is greatest in patients with the most severe heart failure.

In stable patients, it is advisable to add therapy with beta-blocking agents before full target doses of ACE inhibitors are reached. Medication doses should be increased to target as tolerated. Higher doses are more effective than lower doses in preventing hospitalization. Abrupt withdrawal of treatment with an ACE inhibitor may lead to clinical deterioration and should be avoided in the absence of life-threatening complications (e.g., angioedema, hyperkalemia).

Acute Heart Failure and Early Post-Discharge Management

The STRONG-HF trial demonstrated the safety and efficacy of an approach based on starting and titrating oral medical therapy for heart failure within 2 days before anticipated hospital discharge and in early follow-up visits. In haemodynamically stable patients hospitalized for acute HF with elevated NT-proBNP concentrations, high-intensity care involving the rapid intensification of oral HF treatment (including ACE inhibitors) is recommended to reduce HF readmission or all-cause death. The goal of the first titration visit, occurring within 48 hours before discharge, is to reach at least half of the target doses. Titration to full target doses should be attempted within 2 weeks after discharge.

Post-Myocardial Infarction (STEMI)

ACE inhibitors reduce the mortality rate after ST-elevation myocardial infarction (STEMI), and these mortality benefits are additive to those achieved with aspirin and beta blockers. The mechanism involves a reduction in ventricular remodeling after infarction, with a subsequent reduction in the risk of heart failure. ACE inhibitors should be continued indefinitely in patients who have clinically evident HF, a reduction in global LV function, a large regional wall motion abnormality, or hypertension.

Chronic Kidney Disease and Diabetes

In patients with CKD, ACE inhibitor monotherapy provides protection against adverse kidney outcomes, cardiovascular events, cardiovascular death, and all-cause death. Either ACE inhibitors or ARBs should be used to reduce albuminuria and slow the decline in GFR in individuals with type 1 or type 2 diabetes mellitus (DM). For patients with CKD, type 2 DM, and an eGFR >20 mL/min per 1.73 m2, the addition of an SGLT-2 inhibitor while continuing an ACE inhibitor is recommended.

Chronic Coronary Syndromes (CCS)

ACE inhibitors can reduce mortality, MI, stroke, and HF among patients with LV dysfunction, previous vascular disease, and high-risk DM. ACE inhibitors (or ARBs in cases of intolerance) are recommended for the treatment of patients with CCS with co-existing hypertension, LVEF <40%, DM, or CKD, unless contraindicated. However, in CCS patients without HF or high cardiovascular risk, ACE inhibitor therapy is not generally recommended unless required to meet blood pressure targets.

Special Populations and Considerations

• Peri-operative Phase: Continued use of ACE inhibitors is associated with a higher risk of peri-operative hypotension and subsequent end-organ damage. Transient pre-operative interruption of ACE inhibitor therapy is associated with a decreased risk of intra-operative hypotension, though withholding these agents has also been shown to increase post-operative hypertension. ACE inhibitors should be restarted postoperatively as soon as clinically feasible.

• COVID-19: Continuation of ACE inhibitors during COVID-19 illness is recommended, as RCTs have shown no adverse effects on survival and other clinical outcomes.

• Cancer Therapy-Induced Hypertension: ACE inhibitors are the first-line antihypertensive drugs recommended for blood pressure management in patients with cancer.

• Chronic Severe Aortic Regurgitation: ACE inhibitors may provide symptomatic improvement in individuals with chronic severe AR for whom surgery is not feasible or contraindicated. However, they are not recommended for delaying surgery in asymptomatic patients with moderate or severe AR.

Drugs, Doses and Practical Considerations

ACE inhibitors should be initiated in low doses, followed by increments in dose if lower doses have been well tolerated. Titration is generally achieved by doubling doses every 3 to 5 days. The dose should be increased until the doses used are similar to those that have been shown to be effective in clinical trials.

The efficacy of ACE inhibitors represents a so-called class effect. However, it should be emphasized that patients with a low blood pressure (<90 mm Hg systolic) or impaired renal function (serum creatinine >2.5 mg/mL) were not recruited or represented a small proportion of patients in these trials; thus, the efficacy for these populations is less well established.

Relative Benefits of Guideline-Directed Medical Therapies for HFrEF

Angiotensin Receptor Blockers (ARBs) as an Alternative

ARBs are well tolerated in patients who are intolerant of ACE inhibitors because of cough, skin rash, and angioedema. They should be used in symptomatic and asymptomatic patients with an EF <40% who are ACE intolerant for reasons other than hyperkalemia or renal insufficiency (class I indication). ARBs block the effects of angiotensin II on the angiotensin type 1 receptor. ARBs should be initiated with starting doses and uptitrated every 3 to 5 days by doubling the dose. High-dose losartan (150 mg daily) has been shown to be superior to low-dose losartan (50 mg daily) for the composite outcome of death or admission for HF. The combination of an ACE inhibitor and an ARB is not recommended in CKD or any other BP-treatment scenario due to an increased incidence of hyperkalemia and renal adverse effects.

Guideline Recommendations

Blood Pressure Management in CKD

Cancer Therapy-Induced Arterial Hypertension

Prognosis and Follow-up

Long-term follow-up requires serial reassessment with optimized dosing and adherence. In the context of heart failure, particular attention should be paid to symptoms and signs of congestion, blood pressure, heart rate, NT-proBNP values, potassium concentrations, and eGFR.

In CKD, if a patient experiences a sudden decline in kidney function with intensification of antihypertensive therapy, consideration should be given to reducing therapy. With progressive CKD, RAS inhibitors can be continued with careful monitoring. Discontinuing RAS inhibitors in CKD is associated with an increased risk of death or cardiovascular events, though it may lower the incidence of starting kidney replacement therapy. For individuals with a urine albumin-to-creatinine ratio (UACR) >300 mg/g creatinine, a goal of therapy is to reduce the UACR by 30%, repeating the UACR one to four times per year. Nephrology consultation is indicated when the estimated GFR is <30 mL/min per 1.73 m2, albuminuria is >300 mg/g creatinine, or if there are atypical features such as hematuria or rapidly declining renal function.