Renin-angiotensin system blockers may create more risk than reward for sodium-depleted cardiovascular patients with high plasma renin levels.

BACKGROUND: Four recent reports revealed differences in survival rates among treated cardiovascular patients taking renin-angiotensin system-blocking drugs. Patients with higher on-treatment plasma renin activity (PRA) levels died sooner of cardiovascular mortality than those with lower levels. We investigated whether excessive sodium depletion might have induced the higher PRA levels and contributed to the greater morbidity and mortality. METHODS: Using published data, ranges of PRA, blood pressures, drug usage, and biochemical parameters were compared among various groups of cardiovascular patients. RESULTS: We showed (i) that PRA levels are usually medium to low in treated cardiovascular patients, but are sometimes abnormally high, (ii) that excessive sodium depletion can induce such high PRA levels, (iii) that the higher PRA patients exhibited evidence of sodium depletion: lower blood pressures, more frequent natriuretic drug usage, lower N-terminal pro b-type natriuretic peptide (NT-proBNP), and higher blood urea nitrogen and uric acid levels, with similar usage of renin-angiotensin blocking drugs. CONCLUSIONS: We hypothesize that patients with high on-treatment PRA levels die sooner of cardiovascular events because they are excessively sodium-volume depleted. Moreover, renin-angiotensin system-blocking drugs may be harmful in such patients because they can functionally interfere with the effects of reactive rises in PRA that are triggered to prevent potentially dangerous falls in blood pressure, increases in plasma potassium, and falls in glomerular filtration rate. Careful liberalization of salt intake and subtraction of natriuretic drugs, sufficient to reduce reactive hyperreninemia without inducing unacceptable increases in blood pressure, might benefit such patients and decrease risk of adverse effects from drugs that block the renin-angiotensin system.

Plasma renin activity (PRA) levels and antihypertensive drug use in a large healthcare system.

BACKGROUND: Although hypertension guidelines have utility in treating uncomplicated hypertension, they often overlook the pathophysiologic basis and heterogeneity of hypertension. This may explain the relatively poor hypertension control rates. A proposed approach is to guide addition and subtraction of medications using ambulatory plasma renin activity (PRA) values. To evaluate the heterogeneity of hypertension and the medication burden associated with it, we investigated medication usage in relation to PRA among hypertensive patients within a large ethnically diverse organization. METHODS: A cross sectional data analysis was performed of hypertensive subjects with PRA measurements in the Kaiser Permanente Southern California database between 1 January 1998 and 31 October 2009. RESULTS: Among 7,887 such patients 0, 1, 2, ≥3 medication usage was 16%, 20%, 24%, 40% respectively. PRA levels ranged 1000-fold. Across PRA quartiles (Q1 to Q4) ≥3 meds were prescribed to 50%, 40%, 34%, 37%. From low to high PRA quartiles there was no usage trend for angiotensin converting enzyme inhibitors (ACEIs)/ angiotensin receptor blockers (ARBs) (71%), but diuretics increased (52%, 53%, 57%, 68%), calcium channel blocker's (CCB) fell (56%, 53%, 51%, 42%), and ß-blockers fell (77%, 61%, 49%, 41%). Moreover, systolic BP fell (146, 142, 140, 135 mm Hg), blood urea nitrogen (BUN) rose (16, 17, 18, 20 mg/dl), serum uric acid rose (6.1, 6.3, 6.5, 6.9 mg/dl), and chronic kidney disease rose (22%, 22%, 23%, 27%). CONCLUSIONS: Polytherapy was the norm for treating hypertension. Lower PRAs were associated with higher blood pressures and more medications. Higher PRAs were associated with lower pressures and fewer medications. The results indicate that opportunities exist to simplify antihypertensive therapy by using current ambulatory PRA levels to guide drug selections and subtractions.

The plasma renin test reveals the contribution of body sodium-volume content (V) and renin-angiotensin (R) vasoconstriction to long-term blood pressure.

Body sodium works together with the plasma renin-angiotensin system to ensure adequate blood flow to the tissues. Body sodium content determines the extracellular fluid (ECF) volume ensuring that, with each heart beat, a sufficient volume of fluid is delivered into the arterial space. At the same time the kidneys monitor ECF volume and blood pressure (BP), so that the juxtaglomerular cells can adjust their net secretion rate of renin to maintain an appropriate plasma renin activity (PRA) level. Plasma renin produces angiotensin II (Ang II) to constrict the arterioles and thereby ensure sufficient BP to deliver an appropriate rate of flow for cardiovascular homeostasis. The low renin, sodium-volume dependent (V) form of essential hypertension occurs whenever body sodium content increases beyond the point where plasma renin-angiotensin vasoconstrictor activity is turned off. In contrast, medium to high renin (R) hypertension occurs when too much renin is secreted relative to the body sodium content. Thus, BP = V × R. This volume-vasoconstriction dual support of long-term hypertension is validated by the fact that all effective long-term antihypertensive drug types are either (i) natriuretic to reduce body salt and volume content (anti-V), or (ii) antirenin to reduce or block the activity of the circulating renin-angiotensin system (anti-R). The PRA test defines the relative participation of the concurrent volume and vasoconstrictor factors. In the hypertensive patient PRA testing can guide initiation, addition or subtraction of anti-V or anti-R antihypertensive drug types to thereby improve BP control and prognosis while reducing drug type usage and cost.

Enduring direct association of baseline plasma renin activity with all-cause and cardiovascular mortality in hypertensive patients.

BACKGROUND: Plasma renin activity (PRA) has been associated with cardiovascular disease mortality (CVD) events among hypertensive patients. We now report a long-term follow-up to assess the enduring association of PRA to CVD and all-cause mortality. METHODS: Participants (3,791) in a systematic hypertension treatment study had entry systolic blood pressure (BP) ≥140 mm Hg and mean age 52. CVD and all-cause mortality was ascertained for mean of 16 years. Pretreatment PRA was analyzed as a continuous variable, and by tertiles. The 10-year Framingham score was similarly examined. Hazard ratios (HRs) were estimated from multivariate Cox proportional hazard models. RESULTS: There were 804 deaths, and 360 (45%) were CVD. PRA was associated with all-cause mortality and CVD, but not cancer or non-CVD. Although T3 had lower mean baseline and follow-up systolic BP than T1, (146 vs. 152 mm Hg (P < 0.001) and 135 vs. 139 mm Hg (P < 0.001), respectively), T3 had 37% higher all-cause mortality (HR: 1.37, 95% confidence interval (CI): 1.15-1.63, P < 0.001) and 70% higher CVD mortality (HR: 1.70, 95% CI: 1.29-2.23, P < 0.001) after adjustment. The difference between T3 and T1 in mortality from coronary artery disease and myocardial infarction was more pronounced than for all CVD. PRA also significantly improved CVD risk estimation provided by Framingham. CONCLUSIONS: These findings extend and reinforce previous evidence that pretreatment PRA has a significant, independent, specific, and direct long-term association with CVD mortality. Moreover, PRA adds significantly to risk identified by the Framingham score.

A feasibility study of bevacizumab plus dose-dense doxorubicin-cyclophosphamide (AC) followed by nanoparticle albumin-bound paclitaxel in early-stage breast cancer.

PURPOSE: Bevacizumab confers benefits in metastatic breast cancer but may be more effective as adjuvant therapy. We evaluated the cardiac safety of bevacizumab plus dose-dense doxorubicin-cyclophosphamide (ddAC) → nanoparticle albumin-bound (nab)-paclitaxel in human epidermal growth factor receptor 2 normal early-stage breast cancer. EXPERIMENTAL DESIGN: Eighty patients with normal left ventricular ejection fraction (LVEF) were enrolled. Bevacizumab was administered for 1 year, concurrently with ddAC → nab-paclitaxel then as a single agent. LVEF was evaluated at months 0, 2, 6, 9, and 18. This regimen was considered safe if fewer than three cardiac events or fewer than two deaths from left ventricular dysfunction occurred. Correlative studies of cardiac troponin (cTn) and plasma renin activity (PRA) were conducted. RESULTS: The median age was 48 years (range, 27-75 years), and baseline LVEF was 68% (53%-82%). After 39 months' median follow-up (5-45 months): median LVEF was 68% (53%-80%) at 2 months (n = 78), 64% (51%-77%) at 6 months (n = 66), 63% (48%-77%) at 9 months (n = 61), and 66% (42%-76%) at 18 months (n = 54). One patient developed symptomatic LV dysfunction at month 15. Common toxicities necessitating treatment discontinuation were hypertension (HTN, 4%), wound-healing complications (4%), and asymptomatic LVEF declines (4%). Neither cTn nor PRA predicted congestive heart failure (CHF) or HTN, respectively. CONCLUSIONS: Bevacizumab with ddAC → nab-paclitaxel had a low rate of cardiac events; cTn and PRA levels are not predictive of CHF or HTN, respectively. The efficacy of bevacizumab as adjuvant treatment will be established in several ongoing phase III trials.

Pressor responses to antihypertensive drug types.

BACKGROUND: Pressor responses to antihypertensive drugs are not addressed in treatment guidelines although they have been described in various clinical situations. We now report the incidence of pressor responses to initiation of monotherapy using four antihypertensive drug types, and the influence of plasma renin activity (PRA) status, among participants in a worksite-based antihypertensive treatment program. METHODS: Systolic blood pressure (SBP) response was evaluated among 945 participants with no prior treatment who were given either a diuretic or calcium-channel blocker (natriuretic antivolume V drugs, n = 537) or a beta-blocker or angiotensin-converting enzyme (ACE) inhibitor (antirenin R drugs n = 408). PRA was categorized by low, middle, and high tertiles (L, M, and H). SBP rise > or =10 mm Hg was considered pressor. RESULTS: More pressor responses occurred with R than V drugs (11% vs. 5%, P = 0.001). L, M, and H renin tertiles had similar frequencies with V drugs (6, 4, and 6%), but low and middle tertiles given R had greater pressor frequencies (17% P = 0.003 vs. V and 10% P = 0.02 vs. V). Treatment SBP > or =160 mm Hg occurred more frequently with R than V drugs (19% vs. 13%; P = 0.007); moreover, in the lowest renin tertile 35% R vs. 13% V (P = 0.001) had SBP > or =160 mm Hg. Treatment SBP <130 mm Hg was more frequent in V patients in the lowest tertile (18% vs. 5%; P = 0.003), and in R patients in the highest tertile (26% vs. 12%, P = 0.002). CONCLUSIONS: Pressor responses to antihypertensive monotherapy occur sufficiently frequently to be of concern, especially in lower renin patients given a beta-blocker or ACE inhibitor (ACEI).

Plasma Renin test-guided drug treatment algorithm for correcting patients with treated but uncontrolled hypertension: a randomized controlled trial.

BACKGROUND: Undefined pathophysiologic mechanisms likely contribute to unsuccessful antihypertensive drug therapy. The renin test-guided therapeutic (RTGT) algorithm is based on the concept that, irrespective of current drug treatments, subnormal plasma renin activity (PRA) (<0.65 ng/ml/h) indicates sodium-volume excess "V" hypertension, whereas values >or=0.65 indicate renin-angiotensin vasoconstriction excess "R" hypertension. METHODS: The RTGT algorithm was applied to treated, uncontrolled hypertensives and compared to clinical hypertension specialists' care (CHSC) without access to PRA. RTGT protocol: "V" patients received natriuretic anti-"V" drugs (diuretics, spironolactone, calcium antagonists, or alpha(1)-blockers) while withdrawing antirenin "R" drugs (converting enzyme inhibitors, angiotensin receptor antagonists, or beta-blockers). Converse strategies were applied to "R" patients. Eighty-four ambulatory hypertensives were randomized and 77 qualified for the intention-to-treat analysis including 38 in RTGT (63.9 +/- 1.8 years; baseline blood pressure (BP) 157.0 +/- 2.6/87.1 +/- 2.0 mm Hg; PRA 5.8 +/- 1.6; 3.1 +/- 0.3 antihypertensive drugs) and 39 in CHSC (58.0 +/- 2.0 years; BP 153.6 +/- 2.3/91.9 +/- 2.0; PRA 4.6 +/- 1.1; 2.7 +/- 0.2 drugs). RESULTS: BP was controlled in 28/38 (74% (RTGT)) vs. 23/39 (59% (CHSC)), P = 0.17, falling to 127.9 +/- 2.3/73.1 +/- 1.8 vs. 134.0 +/- 2.8/79.8 +/- 1.9 mm Hg, respectively. Systolic BP (SBP) fell more with RTGT (-29.1 +/- 3.2 vs. -19.2 +/- 3.2 mm Hg, P = 0.03), whereas diastolic BP (DBP) declined similarly (P = 0.32). Although final antihypertensive drug numbers were similar (3.1 +/- 0.2 (RTGT) vs. 3.0 +/- 0.3 (CHSC), P = 0.73) in "V" patients, 60% (RTGT) vs. 11% (CHSC) of "R" drugs were withdrawn and BP medications were reduced (-0.5 +/- 0.3 vs. +0.7 +/- 0.3, P = 0.01). CONCLUSIONS: In treated but uncontrolled hypertension, RTGT improves control and lowers BP equally well or better than CHSC, indicating that RTGT provides a reasonable strategy for correcting treated but uncontrolled hypertension.

Aliskiren fails to lower blood pressure in patients who have either low PRA levels or whose PRA falls insufficiently or reactively rises.

BACKGROUND: Suppressed baseline plasma renin activity (PRA) levels or large reactive increases in renin secretion are two possible reasons for treatment failure with antirenin system drugs. METHODS: To investigate their prevalence we reanalyzed data from three published clinical trials of the renin inhibitor aliskiren. RESULTS: Aliskiren failed to lower systolic blood pressure (SBP) by at least 10 mm Hg in half of all patients. It was very effective in two-thirds of medium- to high-renin patients (-19 mm Hg). But BP did not fall in most low-renin patients, or in 30% of medium- to high-renin patients. BP actually rose by >10 mm Hg in 5% of patients taking aliskiren and in >10% of patients when aliskiren was added to an angiotensin receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACEI). PRA changed in parallel with BP. Although PRA fell in most patients, it actually rose in 5% and in up to 30% when aliskiren was added to an ARB or ACEI. CONCLUSIONS: There are two reasons for treatment failure with aliskiren. Many hypertensive patients have large BP falls. But, BP does not fall in most low-renin patients or in medium- to high-renin patients whose PRA levels do not fall sufficiently. If the concept of that treatment resistance is caused by excessive reactive increases in renin secretion is confirmed, then a PRA determination during treatment could be used to guide subsequent addition or subtraction of either natriuretic or antirenin drug types, to thereby correct BP and reduce cardiovascular risk.

Effects of angiotensin receptor blockers on ambulatory plasma Renin activity in healthy, normal subjects during unrestricted sodium intake.

BACKGROUND: Plasma renin activity (PRA), measured under controlled conditions, is a marker of the degree and persistence of renin-angiotensin system blockade. METHODS: Two similarly designed five-way crossover studies evaluated angiotensin II type 1 (AT1) receptor blockade-induced changes in PRA in quietly seated, ambulatory volunteers who were ingesting uncontrolled diets. At weekly intervals, PRA was measured during the 24 h after administration of placebo, olmesartan medoxomil (20 or 40 mg), or valsartan (80 or 160 mg) (Study CS866-445), or placebo, olmesartan medoxomil (40 mg), valsartan (160 or 320 mg), or irbesartan (300 mg) (Study CS866-448). The primary end point was change in PRA relative to placebo from predose to 24 h postdose (DeltaPRA24). RESULTS: In the 20 subjects who completed each study, there was a direct relationship between baseline PRA and DeltaPRA24 for all doses. Subjects with low PRA (<0.65 ng/mL/h) exhibited very low absolute increases in PRA. The DeltaPRA(24) increased significantly with olmesartan medoxomil 20 mg (P<.01) and 40 mg (P<.001) and valsartan 160 mg (P<.05) but not with valsartan 80 mg. In the second study (in which baseline PRA was lower), DeltaPRA24 increased with olmesartan medoxomil 40 mg (P<.0001), valsartan 320 mg (P<.01), and irbesartan 300 mg (P<.01) but not with valsartan 160 mg. The DeltaPRA24 was greatest with olmesartan medoxomil 40 mg and was dose-related for olmesartan medoxomil but not for valsartan. CONCLUSIONS: The greater DeltaPRA24 with olmesartan medoxomil 40 mg indicates a more prolonged AT1 receptor blockade than with valsartan 80, 160, or 320 mg or irbesartan 300 mg. A routine, clinic ambulatory PRA level can be used as a biochemical marker of the persistence and degree of AT1 receptor blockade in subjects without suppressed PRA levels.

Aliskiren, the first renin inhibitor for treating hypertension: reactive renin secretion may limit its effectiveness.

A review of six clinical trials of aliskiren involving >5,000 patients with mild to moderate hypertension indicated that this first of a new class of orally active antihypertensive drugs is no more effective than angiotensin-converting enzyme inhibitors (CEIs), angiotensin receptor blockers (ARBs), or diuretics for lowering blood pressure. The starting dose is 150 mg; 300 mg is usually more effective, but 600 mg is no better than 300 mg. Aliskiren in combination with a diuretic appeared to lower blood pressure more than an aliskiren-ARB combination, but still failed to control blood pressure (<140/90) in 50% of the patients. Although aliskiren suppresses plasma renin activity, it causes much greater reactive rises in plasma renin concentration than does any other antihypertensive class tested. Because aliskiren, like CEIs and ARBs, only blocks 90% to 95% of plasma renin, the pressor consequences of its greater reactive increases in plasma renin concentration appear to offset its net ability to lower blood pressure, especially with higher doses. Patients with hyperreactive renin systems (renovascular, advanced, and malignant hypertension) were excluded from all of the trials. Until the possibility is eliminated of inducing increases in blood pressure with aliskiren in patients with highly reactive renin levels, it seems safe and simple to stick to the less expensive, equally effective and widely available generic CEI drugs for treating the renin factor in hypertension.

Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan and amlodipine: An analysis of findings from the VALUE trial.

BACKGROUND: In the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial the primary outcome (cardiac morbidity and mortality) did not differ between valsartan and amlodipine-based treatment groups, although systolic blood pressure (SBP) and diastolic blood pressure reductions were significantly more pronounced with amlodipine. Stroke incidence was non-significantly, and myocardial infarction was significantly lower in the amlodipine-based regimen, whereas cardiac failure was non-significantly lower on valsartan. OBJECTIVES: The study protocol specified additional analyses of the primary endpoint according to: sex; age; race; geographical region; smoking status; type 2 diabetes; total cholesterol; left ventricular hypertrophy; proteinuria; serum creatinine; a history of coronary heart disease; a history of stroke or transient ischemic attack; and a history of peripheral artery disease. Additional subgroups were isolated systolic hypertension and classes of antihypertensive agents used immediately before randomization. METHODS: The 15,245 hypertensive patients participating in VALUE were divided into subgroups according to baseline characteristics. Treatment by subgroup interaction analyses were carried out by a Cox proportional hazard model. Within each subgroup, treatment effects were assessed by hazard ratios and 95% confidence intervals. RESULTS: For cardiac mortality and morbidity, the only significant subgroup by treatment interaction was of sex (P = 0.016), with the hazard ratio indicating a relative excess of cardiac events with valsartan treatment in women but not in men, but SBP differences in favour of amlodipine were distinctly greater in women. No other subgroup showed a significant difference in the composite cardiac outcome between valsartan and amlodipine-based treatments. For secondary endpoints, a sex-related significant interaction was found for heart failure (P < 0.0001), with men but not women having a lower incidence of heart failure with valsartan. CONCLUSION: As in the whole VALUE cohort, in no subgroup of patients were there differences in the incidence of the composite cardiac endpoint with valsartan and amlodipine-based treatments, despite a greater blood pressure decrease in the amlodipine group. The only exception was sex, in which the amlodipine-based regimen was more effective than valsartan in women, but not in men, whereas the valsartan regimen was more effective in preventing cardiac failure in men than in women.

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial: outcomes in patients receiving monotherapy.

In the main Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) report, we investigated outcomes in 15 245 high-risk hypertensive subjects treated with valsartan- or amlodipine-based regimens. In this report, we analyzed outcomes in 7080 patients (46.4%) who, at the end of the initial drug adjustment period (6 months), remained on monotherapy. Baseline characteristics were similar in the valsartan (N=3263) and amlodipine (N=3817) groups. Time on monotherapy was 3.2 years (78% of treatment exposure time). The average in-trial blood pressure was similar in both groups. Event rates in the monotherapy group were 16% to 39% lower than in the main VALUE trial. In the first analysis, we censored patients when they discontinued monotherapy ("censored"); in the second, we counted events regardless of subsequent therapy (intention-to-treat principle). We also assessed the impact of duration of monotherapy on outcomes. No difference was found in primary composite cardiac end points, strokes, myocardial infarctions, and all-cause deaths with both analyses. Heart failure in the valsartan group was lower both in the censored and intention-to-treat analyses (hazard ratios: 0.63, P=0.004 and 0.78, P=0.045, respectively). Longer duration of monotherapy amplified between-group differences in heart failure. New-onset diabetes was lower in the valsartan group with both analyses (odds ratios: 0.78, P=0.012 and 0.82, P=0.034). Thus, despite lower absolute event rates in monotherapy patients, the relative risks of heart failure and new-onset diabetes favored valsartan. Moreover, these findings support the feasibility of comparative prospective trials in lower-risk hypertensive patients.