The Effect of Angiotensin-Converting Enzyme Inhibitors and Statins on the Progression of Aortic Sclerosis and Mortality

Abstract

Background and aim of the study

Although aortic sclerosis has been associated with an increase in adverse cardiovascular outcomes, no proven therapy has been shown to slow its progression to overt aortic stenosis (AS). Thus, the hypothesis was assessed that treatment with angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs) or statins may be associated with an improvement in the clinical outcome of these patients.

Methods

A total of 4,105 patients with evidence of aortic sclerosis seen on transthoracic echocardiography (defined as thickening or calcification with a mean valve gradient ≤15 mmHg) was identified. Patients with a sclerotic valve who were treated with ACE-Is/ARBs or statins were followed for a mean period of 1,078 ± 615 days. After adjustment for the propensity to receive ACE-Is/ARBs or statins, mortality, hemodynamic progression to AS, hospitalization for ischemic heart disease (IHD), and congestive heart failure (CHF) were assessed and related to the medical treatment.

Results

At baseline, patients with aortic sclerosis who were treated with an ACE-I/ARB or a statin suffered significantly more from comorbidities such as IHD, CHF, hypertension, diabetes, and peripheral arterial disease, when compared to subjects with sclerotic valves not treated with these drugs. After adjustment for confounding factors, treatment with statins was associated with a significant reduction in mortality (odds ratio [OR] 0.73, 95% CI 0.56–0.98, p = 0.001), admission for IHD (OR 0.81, 95% CI 0.66–0.99, p = 0.03), admission for CHF (OR 0.68, 95% CI 0.55–0.85, p = 0.01) and progression to AS (OR 0.64, 95% CI 0.42–0.97, p = 0.03). While ACE-I treatment resulted in a significant reduction in admission for IHD (OR 0.80, 95% CI 0.65–0.98, p = 0.03) and CHF (OR 0.76, 95% CI 0.62–0.94, p = 0.01), the beneficial trend towards reduced mortality and delayed progression to AS was not significant.

Conclusion

Treatment of this patient population with statins led to a significant reduction in mortality and also slowed the progression to AS - an effect that was not statistically significant with ACE-I treatment.

Aortic sclerosis is the most common valvular disease in the Western world, and its incidence is known to increase with age (1). It is a progressive disease with a continuum that begins with evidence of calcium deposition on the valve (aortic sclerosis) that may, ultimately, transform into an obstruction of flow from the left ventricle in association with ventricular remodeling, hemodynamic compromise, symptoms, and death. The results of recent studies have shown that the development of aortic stenosis (AS) is not due simply to wear-and-tear of the valve, but also involves chronic inflammatory infiltrates, the deposition of atherosclerotic lipoproteins, and calcification – which is similar in process to coronary artery disease (CAD) (2). In fact, AS often coexists in patients with underlying CAD, as they share many risk factors (3,4).

Recent observations regarding the many shared characteristics between aortic sclerosis and CAD have prompted investigations into the medical interventions that may have a salutary effect on both conditions (5). For example, aggressive lipid-lowering agents (i.e., statins) and the pro-remodeling antihypertensive agents – namely angiotensin-converting enzymes (ACE-Is) or angiotensin receptor blockers (ARBs) - have both been postulated to have a protective effect on aortic valve lesion progression, given their beneficial effects on cardiovascular mortality and morbidity in CAD patients (6,7). However, there is no clinical evidence to date demonstrating an effective medical therapy for patients with aortic sclerosis or AS. In fact, previous studies on the role of statins and ACE-Is on the progression of AS have reported conflicting results, with recent prospective clinical trials having shown no clear benefit for the use of statins in patients with AS. However, the effects of statins at an earlier stage in the disease process (aortic valve sclerosis) remain to be determined.

The early stages of calcific aortic valve disease, when valvular stiffening and obstruction to flow have not yet developed, may provide a window for medical intervention. The aim of the present study was to determine whether the use of statins or ACE-Is/ARBs in patients with early-stage aortic sclerosis was associated with a reduction in the rate of progression, an enhancement of clinical outcome, and an improved survival.

Clinical material and methods

Patient selection

Between 1998 and 2008, a total of 4,105 patients was identified with aortic sclerosis by using transthoracic echocardiography (TTE) at the one of three laboratories within the VA Palo Alto Health Care System. Aortic sclerosis was defined as the presence of aortic valve calcification or thickening on TTE, with a mean gradient <15 mmHg. Exclusion criteria included the presence of a prosthetic aortic valve, and a lack of any outpatient prescriptions during the 180-day period prior to echocardiography.

Approval to conduct the study was granted by the institutional review board at Stanford University.

Echocardiography

Each patient underwent TTE that included two-dimensional (2D), pulsed-wave, continuous-wave and color Doppler (Agilent Sonos 5500 and 2500 ultrasound systems). The 2D assessment of the aortic valve was performed on the basis of the parasternal long-axis and short-axis views. Peak and mean aortic valve pressure gradients were calculated using the modified Bernoulli equation, and the aortic valve area was calculated using the continuity equation.

Medical therapy and diagnoses

At study entry, the following clinical data were acquired: age, gender, baseline creatinine level, and ventricular function (systolic heart failure was defined as a left ventricular ejection fraction <50%). Furthermore, other comorbid conditions such as prior diagnosis of diabetes mellitus, peripheral vascular disease, hypertension, and a history of ischemic heart disease (IHD) were assessed based on recorded ICD-9 codes. The use of statins, ACE-Is, ARBs, calcium channel blockers and β-blockers was defined as a filled prescription within 12 months before the index echocardiogram.

Clinical outcome

The primary outcome of total mortality was obtained from the Social Security Death Index and VA death records. Other clinical end-points included a progression to AS, and hospitalization for IHD or heart failure. AS was defined as a sclerotic valve, 2D evidence of restricted motion, and a mean gradient ≥15 mmHg.

Statistical analysis

The Pearson chi-square analysis was used to evaluate categorical variables, and -tests were used to evaluate differences in continuous variables. The primary comparison was the association of treatment with and without ACE-Is/ARBs or statins and survival. A Kaplan-Meier survival analysis was used to determine differences in mortality. A Cox proportional hazards analysis was employed to adjust the treatment-outcome association for differences in baseline patient characteristics.

Propensity score

Logistic regression was used to determine the propensity to receive ACE-Is/ARBs or statins. This non-parsimonious model included all available patient characteristics, medication use, and laboratory values. Cox proportional hazards analyses were then used to evaluate the association between ACE-I/ARB or statin use, and total mortality after adjustment for the propensity to receive such therapy. Logistic regression was used to compare the association between ACE-Is/ARBs or statins use and secondary end-points, adjusting for the propensity to receive an ACE-I/ARB or a statin. The propensity score was incorporated into these analyses both as a continuous variable and by stratified categorical quartiles. A p-value <0.05 was considered to be statistically significant. Statistical analyses were performed using the STATA program (version 9.0; College Station, TX, USA).

Results

Baseline characteristics

Of the 4,105 subjects initially identified, 1,641 (40%) underwent follow up echocardiography and formed the cohort for the analysis of disease progression. The baseline characteristics of all enrolled patients with sclerotic valves, according to treatment with ACE-Is/ARBs or statins, are detailed in Table I. Bicuspid aortic valve was documented in only eight patients on ACE-Is/ARBs, in 13 patients off ACE-Is/ARBs (p <0.05), and in four patients on statins and 17 patients off statins (p <0.05). Patients taking ACE-Is/ARBs or statins had a prior diagnosis of hypertension, diabetes mellitus, or IHD more frequently than those not taking these medications. The use of other medications (e.g., beta-blockers and calcium-channel blockers) was also higher in patients treated with ACE-Is/ARBs or statins compared to those not treated. Hyperlipidemia, defined as low-density lipoprotein serum level ≥130 mg/dl, was found to be present in 278/1,265 (22%) of those taking ACE-Is/ARBs, and in 247/949 (26%) of those not taking ACE-Is/ARBs (p = 0.03). Similarly, 306/1,232 (25%) and 219/989 (22%) of the patients were found to have hyperlipidemia when compared to those taking statins and not taking statins, respectively (p = 0.16).

Table I.

Baseline characteristics of patients with sclerotic valves who were treated with or without statins or ACE-I/ARBs.

Characteristic	Statins		p-value*	ACE-I		p-value+
	Treatment (n = 1,689)	No treatment (n = 2,416)		Treatment (n = 2,017)	No treatment (n = 2,088)
Age (years)	72	71	0.024	72	71	<0.001
Female gender	41 (2)	95 (4)	0.008	49 (2)	87 (4)	0.002
IHD	1141 (68)	763 (32)	<0.001	1145 (57)	759 (36)	<0.001
HTN	1502 (89)	1553 (64)	<0.001	1864 (92)	1191 (57)	<0.001
DM	741 (44)	620 (26)	<0.001	982 (49)	379 (18)	<0.001
CHF	476 (28)	589 (24)	0.006	710 (35)	355 (17)	<0.001
PAD	119 (7)	104 (4)	<0.001	124 (6)	99 (5)	0.047
Prior MI#	225 (14)	389 (17)	0.007	343 (17)	271 (13)	0.008
Mean LVEF (%)	53	53	0.78	52	54	<0.001
Drug therapy
Beta-blockers	882 (52)	563 (23)	<0.001	912 (45)	533 (25)	<0.001
Ca-ch. blockers	599 (36)	536 (22)	<0.001	717 (36)	418 (20)	<0.001
ACE-I/ARBs	1152 (68)	866 (36)	<0.001	-	-	-
Statins	-	-	-	1151 (57)	538 (26)	<0.001

^*Statin treatment versus no treatment;

⁺ACE-I treatment versus no treatment;

^#troponin level > 0.2.

Values in parentheses are percentages.

ACE-I: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocker; CHF: Congestive heart failure; DM: Diabetes mellitus; HTN: Hypertension; IHD: Ischemic heart disease;

LVEF: Left ventricular ejection fraction; MI: Myocardial infarction; PAD: Peripheral arterial disease.

Unadjusted survival

Unadjusted survival during a mean follow up of 3.0 ± 1.7 years showed an association between enhanced survival and statin use (81% survival among patients treated with statins versus 74% survival among those not treated with statins at three years; p <0.001). Treatment with ACE-Is/ARBs was not significantly associated with survival.

Adjusted survival

Given the differences in baseline characteristics between patients who were receiving either statin or ACE-I/ARB therapy, a propensity score was created for the use of each treatment. Factors that significantly predicted the probability of patients being treated with ACE-Is/ARBs included a prior history of diabetes mellitus, hypertension, and heart failure, while only a history of IHD and peripheral arterial disease were significant predictors of statin use. After adjustment using the propensity scores, an improved survival remained significantly associated with the use of statins, but not with ACE-Is/ARBs (Fig. 1A and B).

Figure 1.

Survival adjusted for the propensity to receive (A) ACE-I/ARB or (B) statins is shown for patients with and without treatment. Treatment with ACE-I/ARB and statins was significantly associated with an improved survival (p <0.001) compared to those patients not treated.

Other outcomes

Other outcomes are summarized by the use of ACE-Is/ARBs (Table II) and statins (Table III). Hemodynamic progression, as defined by the development of AS or a need for aortic valve replacement (AVR), was significantly lower in patients treated with statins, a trend that was not observed with ACE-I/ARB treatment. Both, statin and ACE-I/ARB treatment resulted in significant reduction in admission for CHF or IHD, after adjustment for confounding factors (Fig. 2A and B).

Table II.

Clinical outcomes in patients with aortic sclerosis who were treated with or without ACE-I/ARB.

End-point	ACE-I/ARB	No ACE-I/ARB	p-value
Death
90-day mortality	58/1889 (3)	60/1805 (3)	0.66
1-year mortality	177/1668 (11)	172/1530 (11)	0.57
Heart failure hospitalization	300/2017 (15)	289/2088 (14)	0.34
IHD events	488/2017 (24)	482/2088 (23)	0.40
AVR	9/2017 (0.4)	20/2088 (1)	0.05
Progression to AS	67/2017 (4)	75/2088 (3)	0.64
Cerebrovascular accident	79/2017 (4)	69/2088 (3)	0.29

Values in parentheses are percentages.

AS: Aortic stenosis; AVR: Aortic valve replacement. Other abbreviations as Table I.

Table III.

Clinical outcomes in patients with aortic sclerosis who were treated with or without statins.

End-point	Statins	No statins	p-value
Death
90-day mortality	39/1583 (2)	79/2111 (4)	0.029
1-year mortality	120/1364 (9)	229/1834 (12)	0.001
Heart failure hospitalization	197/1689 (12)	392/2416 (16)	<0.001
IHD events	439/1689 (26)	531/2416 (22)	0.003
AVR	5/1689 (0.3)	24/2416 (1)	0.009
Progression to AS	49/1689 (3)	93/2416 (4)	0.102
Cerebrovascular accident	62/1689 (4)	86/2416 (4)	0.851

Values in parentheses are percentages.

Abbreviations as Table I.

Figure 2.

Odds ratios for (A) statin and (B) ACE-I/ARB use (unadjusted outcomes shown as open diamonds; adjusted outcomes shown as filled diamonds). ‘Progression’ refers to aortic valve replacement or progression to aortic stenosis.

Discussion

Aortic sclerosis is a progressive disease that is characterized by a long asymptomatic phase which often lasts for several decades, followed by a shorter symptomatic phase associated with a progressive narrowing of the orifice of the valve (1,2). Once symptoms due to stenosis occur, however, the prognosis is poor and AVR is mandated (8). Mortality is significantly high in patients with inoperable AS who are also ineligible for percutaneous AVR. While conflicting retrospective reports exist on the utility of medical therapy, there is currently no definitive therapy supported by prospective studies to delay the progression of AS (9–14). The results of the present study provide valuable clinical outcome on patients with aortic sclerosis (but not stenosis) when treated with statins and ACE-Is/ARBs. In this case it was shown that, in patients with AS, statins and ACE-Is were associated with an improved outcome, including significant reductions in admissions for IHD (ACE-Is, statins), admissions for heart failure (ACE-Is, statins), progression to AS (statins) and total mortality (statins). Whether aortic sclerosis is a marker of increased risk for mortality, or has a direct effect on clinical outcome, is unclear. Nonetheless, it has been shown that once these patients have been identified, then treatment with statins or ACE-Is is associated with a reduction in cardiac events.

The mechanism of the observed beneficial effect of statins and ACE-Is/ARBs in patients with aortic sclerosis is not entirely clear, but may depend on the vascular and myocardial protective effects of these drugs (15). Numerous randomized clinical trials have shown statins to be an effective therapy for the primary and secondary prevention of CAD (16), with some of the beneficial effects of statins perhaps occurring independently of their effect on lipid profiles. Among the many properties of statins (besides a disruption in cholesterol biosynthesis) has been demonstrated an ability to down-regulate the expression of numerous inflammatory cytokines, to inhibit calcification processes, and to enhance endothelial nitric oxide synthase activity (17). Whether statins have a direct effect on aortic valve pathology by altering the inflammatory milieu, independent of any cholesterol-lowering effect, remains unclear. ACE-Is/ARBs have also been shown to have a myriad of beneficial properties, such as promoting vasodilation, limiting neurohormonal activation, improving endothelial function, delaying the development of atherosclerosis, and reversing negative vascular remodeling. Furthermore, tissue ACE inhibition could potentially influence the pathologic process in the valve leaflets themselves, similar to the effects observed in atherosclerotic plaques. The results of recent studies have demonstrated the presence of ACE and increased angiotensin (AT) receptors in aortic valve lesions (18,19). When considering the similarities between AS and atherosclerosis at both cellular and tissue levels, it is reasonable to postulate that the inhibition of ACE and the blocking of AT receptors may have an effect on the development of AS.

Previous randomized controlled trials of statins in patients with moderate-to-severe AS have failed to demonstrate any reduction in the progression of disease (11,14,20–26). Despite initially addressing aortic sclerosis, the findings of the present study were consistent with the results of previous retrospective studies which showed that statin therapy may slow the hemodynamic progression of aortic valve lesions (13,20–24). However, it was shown for the first time that a beneficial effect may be exerted in subclinical aortic valve disease, which in turn suggests that statins/ACE-Is may have a protective effect when administered at a time before a fixed lesion has developed. However, it is possible that any important health benefit from statin therapy in those patients with aortic sclerosis may derive from a reduction in mortality or IHD, as opposed to a lesser development of AS.

Evidence behind the use of ACE-Is or ARBs in patients with aortic sclerosis or stenosis is even more scarce. Since no prospective studies of the use of ACE-I or ARB treatments in patients with AS have yet been reported, a randomized clinical trial in which the effect of statins and ACE-Is/ARBs on the progression of AS development and overall survival benefit are assessed is warranted, before these agents become an accepted therapeutic strategy.

Study limitations

The primary limitation of the present study was its observational nature, which rendered it subject to confounding. In the present study, patients treated with ACE-Is appeared to be more poorly than those not treated; hence, when adjustments were made for observable patient characteristics using a propensity score, the association between ACE-I treatment and improved outcome became stronger. It is reasonable to assume that, if the unobserved covariates could also have been adjusted, then the association would have been even greater. A further limitation was that the study population consisted predominantly of males, and that these results may not be applicable to females. The study was powered to detect a large mortality benefit; thus, it is possible that small to moderate (though clinically important) changes in outcome - including progression to AS with ACE-Is and ARBs - may exist but could not be detected with the sample size available. Furthermore, some patients with mild degrees of AS may have been included, while others may have progressed to AS but were not detected due to a lack of echocardiography. In addition, the present study failed to address whether the beneficial effect of statins is a result of their lipid-lowering action. Finally, no differentiation was made between the use of ACE-Is and ARBs, or the impact of dose.

In conclusion, it has been shown that the treatment of patients with aortic sclerosis with statins or ACE-Is is associated with an improved clinical outcome. The use of statins was significantly associated with a reduced mortality and progression to AS or AVR, while ACE-I/ARB therapy resulted in a similar favorable trend, though this was not statistically significant. Both agents were associated with a significant reduction in hospitalization for IHD and heart failure. While these results were consistent with those of prior studies which suggested that aortic sclerosis should be considered a CAD equivalent, further randomized trials should be conducted to confirm the treatment effects of statins and ACE-Is in patients with aortic sclerosis.