ABSTRACT: Antihypertensive drugs are commonly used in cardiovascular diseases (CVD), less is known about the comparative effectiveness of different antihypertensive drugs on stroke events in CVD patients. We searched MEDLINE, EMBASE, the Cochrane Library, and the Web of Science for randomized controlled trails comparing the different antihypertensive drugs for stroke events in CVD patients from inception until November, 2022. Pairwise and network meta-analysis were performed to compare of different antihypertensive drugs for the incidence of stroke events in CVD patients. The protocol was registered on the PROSPERO database (CRD42022375038). 33 trials involving 141,217 CVD patients were included. The incidence of stroke in CVD patients for each antihypertensive drugs was placebo (3.0%), ACEI (2.4%), ARB (4.1%), CCB (1.8%), β blocker (1.3%), and diuretic (3.6%). Antihypertensive drug was significantly reducing stroke events in CVD patients when compared with placebo (OR 0.82; 95% CI 0.75 to 0.89). Specifically, ACEI (OR 0.82; 95% CI 0.69 to 0.97), ARB (OR 0.87; 95% CI 0.77 to 0.98), CCB (OR 0.69; 95% CI 0.54 to 0.87), and diuretic (OR 0.74; 95% CI 0.57 to 0.95) were significantly reducing stroke events in CVD patients when compared with placebo. Network meta-analysis suggested CCB and diuretic ranked the first and second in reducing the incidence of stroke events in CVD patients with the SUCRA value of 90.9% and 73.8%. CCB and diuretic had the greatest possibility to reduce the incidence of stroke events in CVD patients, while, ACEI was the worst antihypertensive agents in reducing the incidence of stroke events in CVD patients.
BACKGROUND: The blood pressure (BP) threshold for initial pharmacological treatment remains controversial. The number needed to treat (NNT) is a significant indicator. This study aimed to explore the benefits and risks of antihypertensive medications in participants with different systolic BPs (SBPs), and cardiovascular disease status from the perspective of the NNT.
METHODS: We conducted a meta-analysis of 52 randomized placebo-controlled trials. The data were extracted from published articles and pooled to calculate NNTs. The participants were divided into five groups, based on the mean SBP at entry (120-129.9, 130-139.9, 140-159.9, 160-179.9, and ≥180 mmHg). Furthermore, we stratified patients into those with and without cardiovascular disease. The primary outcomes were the major adverse cardiovascular events (MACEs), and adverse events (AEs) leading to discontinuation.
RESULTS: Antihypertensive medications were not associated with MACEs, however, it increased AEs, when the SBP was <140 mmHg. For participants with cardiovascular disease or at a high risk of heart failure and stroke, antihypertensive treatment reduced MACEs when SBP was ≥130 mmHg. Despite this, only 2-4 subjects had reduced MACEs per 100 patients receiving antihypertensive medications for 3.50 years. The number of individuals who needed to treat to avoid MACEs declined with an increased cardiovascular risk.
CONCLUSION: Pharmacological treatment could be activated when SBP reaches 140 mmHg. For people with cardiovascular disease or at a higher risk of stroke and heart failure, 130 mmHg may be a better therapeutic threshold. It could be more cost-effective to prioritize antihypertensive medications for people with a high risk of developing cardiovascular disease.
BACKGROUND: Use of drug combinations is recommended by hypertension guidelines for most patients because of the greater blood pressure (BP)-lowering effect compared with monotherapy. However, no evidence is available on outcome benefits of treatment strategies based on drug combinations vs. simpler treatment regimens, using data from randomized clinical trials (RCTs). We evaluated drug combination therapies of different complexity.
METHODS: Electronic databases were searched for BP-lowering RCTs that compared combination treatment or monotherapy vs. placebo, no-treatment or less-complex treatment. Combination treatment was considered as follows: background treatment continued during follow-up on top of the trial drug(s) of interest and drug(s) were added to the initial drug(s) of interest in the majority of the patients. Monotherapy was considered whenever pre-randomization treatment was withdrawn or absent and a single drug was administered at randomization. Complexity of treatment indicates the higher averaged number of daily medications used in the eligible RCTs.
RESULTS: We selected 93 trials (290 304 patients; follow-up, 3.9 years). The on-treatment mean number of drugs was 2.10 and 0.99 in the more and less actively treated patients, respectively. Compared with placebo, no-treatment or less-complex treatment, combination treatments of any complexity (mean number of drugs, 1.40 vs. 0.41, 2.32 vs. 0.48, 2.56 vs. 1.62 and 3.14 vs. 2.19) were associated with reduction of all or most fatal and nonfatal outcomes. There was also an increased rate of side effects leading to treatment discontinuation, although in absolute numbers the benefit usually prevailed.
CONCLUSION: These data provide randomized-based trial evidence that antihypertensive combination treatment up to three or more drugs is protective. The net benefit, however, may be attenuated when side effects are considered.
Background and Purpose The present study aimed to compare the efficacy and tolerability of different blood pressure (BP)-lowering strategies. Methods Randomized controlled trials that compared various antihypertensive treatments and stroke outcomes were included. Eligible trials were categorized into three scenarios: single or combination antihypertensive agents against placebos; single or combination agents against other agents; and different BP-lowering targets. The primary efficacy outcome was the risk reduction pertaining to strokes. The tolerability outcome was the withdrawal of drugs, owing to drug-related side effects (PROSPERO registration number CRD42018118454 [20/12/2018]). Results The present study included 93 trials (average follow-up duration, 3.3 years). In the pairwise analysis, angiotensin-converting enzyme inhibitors (ACEis) and beta-blockers (BBs) were inferior to calcium channel blockers (CCBs) (odds ratio [OR], 1.123; 95% confidence interval [CI], 1.008 to 1.252) (OR, 1.261; 95% CI, 1.116 to 1.425) for stroke prevention, BB was inferior to angiotensin II receptor blockers (ARB) (OR, 1.361; 95% CI, 1.142 to 1.622), and diuretics were superior to ACEi (OR, 0.871; 95% CI, 0.771 to 0.984). The combination of ACEi+CCB was superior to ACEi+diuretic (OR, 0.892; 95% CI, 0.823 to 0.966). The network meta-analysis confirmed that diuretics were superior to BB (OR, 1.34; 95% CI, 1.11 to 1.58), ACEi+diuretic (OR, 1.47; 95% CI, 1.02 to 2.08), BB+C-CB (OR, 2.05; 95% CI, 1.05 to 3.79), and renin inhibitors (OR, 1.87; 95% CI, 1.25 to 2.75) for stroke prevention. Regarding the tolerability profile, the pairwise analysis revealed that ACEi was inferior to CCB and less tolerable, compared to the other treatments. Conclusions Monotherapy using diuretics, CCB, or ARB, and their combinations could be employed as first-line treatments for stroke prevention in terms of efficacy and tolerability.
BACKGROUND: Angiotensin receptor blockers (ARBs) are commonly used as a treatment for many cardiovascular diseases, but their safety has been called into question. The VALUE trial found an increased risk of myocardial infarction in participants receiving ARBs compared to other antihypertensive. The aim of the meta-analysis was to synthetize the available evidence of randomised controlled trials (RCTs) and elucidate if ARBs increase the risk of cardiovascular events.
METHODS: A comprehensive search was conducted to identify RCTs that assessed the safety of ARBs. Titles and abstracts of all papers were independently screened by two authors. Data extraction and quality assessment were also performed independently. The relative risk (RR) of all-cause mortality, myocardial infarction, and stroke were pooled using the IVhet model. Multiple sensitivity analyses were conducted to assess the effect of ARBs by restricting the analysis to different participants' characteristics.
RESULTS: Forty-five RCTs comprising of 170,794 participants were included in the analysis. The pooled estimates revealed that ARBs do not increase the risk of all-cause mortality (RR 1.00; 95%CI 0.97-1.04), myocardial infarction (RR 1.01; 95%CI 0.96-1.06), and stroke (RR 0.92; 95%CI 0.83-1.01). The sensitivity analysis did not yield a particular group of patients at increased risk of cardiovascular events with ARBs. Risk of all-cause mortality and stroke decreased with ARB when the proportion of smokers in a population was < 25% (RR 0.91; 95%CI 0.84-0.98) and in females (RR 0.76; 95%CI 0.68-0.84), respectively.
CONCLUSIONS: ARBs do not increase the risk of major cardiovascular events and are safe for use in patients.
BACKGROUND: Approximately half of people with heart failure have chronic kidney disease (CKD). Pharmacological interventions for heart failure in people with CKD have the potential to reduce death (any cause) or hospitalisations for decompensated heart failure. However, these interventions are of uncertain benefit and may increase the risk of harm, such as hypotension and electrolyte abnormalities, in those with CKD.
OBJECTIVES: This review aims to look at the benefits and harms of pharmacological interventions for HF (i.e., antihypertensive agents, inotropes, and agents that may improve the heart performance indirectly) in people with HF and CKD.
SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies through 12 September 2019 in consultation with an Information Specialist and using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA: We included randomised controlled trials of any pharmacological intervention for acute or chronic heart failure, among people of any age with chronic kidney disease of at least three months duration.
DATA COLLECTION AND ANALYSIS: Two authors independently screened the records to identify eligible studies and extracted data on the following dichotomous outcomes: death, hospitalisations, worsening heart failure, worsening kidney function, hyperkalaemia, and hypotension. We used random effects meta-analysis to estimate treatment effects, which we expressed as a risk ratio (RR) with 95% confidence intervals (CI). We assessed the risk of bias using the Cochrane tool. We applied the GRADE methodology to rate the certainty of evidence.
MAIN RESULTS: One hundred and twelve studies met our selection criteria: 15 were studies of adults with CKD; 16 studies were conducted in the general population but provided subgroup data for people with CKD; and 81 studies included individuals with CKD, however, data for this subgroup were not provided. The risk of bias in all 112 studies was frequently high or unclear. Of the 31 studies (23,762 participants) with data on CKD patients, follow-up ranged from three months to five years, and study size ranged from 16 to 2916 participants. In total, 26 studies (19,612 participants) reported disaggregated and extractable data on at least one outcome of interest for our review and were included in our meta-analyses. In acute heart failure, the effects of adenosine A1-receptor antagonists, dopamine, nesiritide, or serelaxin on death, hospitalisations, worsening heart failure or kidney function, hyperkalaemia, hypotension or quality of life were uncertain due to sparse data or were not reported. In chronic heart failure, the effects of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) (4 studies, 5003 participants: RR 0.85, 95% CI 0.70 to 1.02; I2 = 78%; low certainty evidence), aldosterone antagonists (2 studies, 34 participants: RR 0.61 95% CI 0.06 to 6.59; very low certainty evidence), and vasopressin receptor antagonists (RR 1.26, 95% CI 0.55 to 2.89; 2 studies, 1840 participants; low certainty evidence) on death (any cause) were uncertain. Treatment with beta-blockers may reduce the risk of death (any cause) (4 studies, 3136 participants: RR 0.69, 95% CI 0.60 to 0.79; I2 = 0%; moderate certainty evidence). Treatment with ACEi or ARB (2 studies, 1368 participants: RR 0.90, 95% CI 0.43 to 1.90; I2 = 97%; very low certainty evidence) had uncertain effects on hospitalisation for heart failure, as treatment estimates were consistent with either benefit or harm. Treatment with beta-blockers may decrease hospitalisation for heart failure (3 studies, 2287 participants: RR 0.67, 95% CI 0.43 to 1.05; I2 = 87%; low certainty evidence). Aldosterone antagonists may increase the risk of hyperkalaemia compared to placebo or no treatment (3 studies, 826 participants: RR 2.91, 95% CI 2.03 to 4.17; I2 = 0%; low certainty evidence). Renin inhibitors had uncertain risks of hyperkalaemia (2 studies, 142 participants: RR 0.86, 95% CI 0.49 to 1.49; I2 = 0%; very low certainty). We were unable to estimate whether treatment with sinus node inhibitors affects the risk of hyperkalaemia, as there were few studies and meta-analysis was not possible. Hyperkalaemia was not reported for the CKD subgroup in studies investigating other therapies. The effects of ACEi or ARB, or aldosterone antagonists on worsening heart failure or kidney function, hypotension, or quality of life were uncertain due to sparse data or were not reported. Effects of anti-arrhythmic agents, digoxin, phosphodiesterase inhibitors, renin inhibitors, sinus node inhibitors, vasodilators, and vasopressin receptor antagonists were very uncertain due to the paucity of studies.
AUTHORS' CONCLUSIONS: The effects of pharmacological interventions for heart failure in people with CKD are uncertain and there is insufficient evidence to inform clinical practice. Study data for treatment outcomes in patients with heart failure and CKD are sparse despite the potential impact of kidney impairment on the benefits and harms of treatment. Future research aimed at analysing existing data in general population HF studies to explore the effect in subgroups of patients with CKD, considering stage of disease, may yield valuable insights for the management of people with HF and CKD.
ABSTRACT: Uncertainties still remain in terms of the efficacy of anti-hypertensive treatment on the risk of major cardiovascular (CV) events within prehypertensive levels. This review aims to assess the efficacy and safety of anti-hypertensives on the CV risks in populations within prehypertensive levels. Randomized controlled trials (RCTs) concerning active treatment vs placebo in populations within prehypertensive levels were identified through electronic database and manual search. Outcomes included the first co-primary outcomes, stroke, heart failure (HF), myocardial infarction (MI), all-cause mortality, and cardiovascular mortality. The first co-primary outcomes were defined as composite cardiovascular disease (CVD) events in the included studies. A total of 29 RCTs involving 127,641 participants were identified. Pooled analysis showed active treatment was associated with a significant 7% reduction in risk of the first co-primary outcomes, 14% in stroke, and 10% in HF as compared to placebo (0.86, 0.77-0.96; 0.93, 0.89-0.98; and 0.90, 0.83-0.97). However, there were no significant reductions in risk of MI, all-cause mortality, and cardiovascular mortality. A significant reduction in risk of the first co-primary outcomes was observed in subpopulations with systolic blood pressure (SBP) 130-139 mmHg (0.94, 0.89-0.99) or prior CVDs (0.88, 0.82-0.94). Meta-regression analyses showed no significant relative risk reductions proportional to the magnitude of the mean baseline BP, mean on-treatment BP, the mean absolute change in BP, the proportion of patients with hypertension, and mean age. In summary, anti-hypertensive treatment has beneficial cardiovascular effects in populations within prehypertensive levels, especially in subpopulations with SBP 130-139 mmHg or prior CVDs.
BACKGROUND: The benefits of blood pressure lowering treatment for prevention of cardiovascular disease are well established. However, the extent to which these effects differ by baseline blood pressure, presence of comorbidities, or drug class is less clear. We therefore performed a systematic review and meta-analysis to clarify these differences.
METHOD: For this systematic review and meta-analysis, we searched MEDLINE for large-scale blood pressure lowering trials, published between Jan 1, 1966, and July 7, 2015, and we searched the medical literature to identify trials up to Nov 9, 2015. All randomised controlled trials of blood pressure lowering treatment were eligible for inclusion if they included a minimum of 1000 patient-years of follow-up in each study arm. No trials were excluded because of presence of baseline comorbidities, and trials of antihypertensive drugs for indications other than hypertension were eligible. We extracted summary-level data about study characteristics and the outcomes of major cardiovascular disease events, coronary heart disease, stroke, heart failure, renal failure, and all-cause mortality. We used inverse variance weighted fixed-effects meta-analyses to pool the estimates.
RESULTS: We identified 123 studies with 613 815 participants for the tabular meta-analysis. Meta-regression analyses showed relative risk reductions proportional to the magnitude of the blood pressure reductions achieved. Every 10 mm Hg reduction in systolic blood pressure significantly reduced the risk of major cardiovascular disease events (relative risk [RR] 0·80, 95% CI 0·77-0·83), coronary heart disease (0·83, 0·78-0·88), stroke (0·73, 0·68-0·77), and heart failure (0·72, 0·67-0·78), which, in the populations studied, led to a significant 13% reduction in all-cause mortality (0·87, 0·84-0·91). However, the effect on renal failure was not significant (0·95, 0·84-1·07). Similar proportional risk reductions (per 10 mm Hg lower systolic blood pressure) were noted in trials with higher mean baseline systolic blood pressure and trials with lower mean baseline systolic blood pressure (all ptrend>0·05). There was no clear evidence that proportional risk reductions in major cardiovascular disease differed by baseline disease history, except for diabetes and chronic kidney disease, for which smaller, but significant, risk reductions were detected. β blockers were inferior to other drugs for the prevention of major cardiovascular disease events, stroke, and renal failure. Calcium channel blockers were superior to other drugs for the prevention of stroke. For the prevention of heart failure, calcium channel blockers were inferior and diuretics were superior to other drug classes. Risk of bias was judged to be low for 113 trials and unclear for 10 trials. Heterogeneity for outcomes was low to moderate; the I(2) statistic for heterogeneity for major cardiovascular disease events was 41%, for coronary heart disease 25%, for stroke 26%, for heart failure 37%, for renal failure 28%, and for all-cause mortality 35%.
INTERPRETATION: Blood pressure lowering significantly reduces vascular risk across various baseline blood pressure levels and comorbidities. Our results provide strong support for lowering blood pressure to systolic blood pressures less than 130 mm Hg and providing blood pressure lowering treatment to individuals with a history of cardiovascular disease, coronary heart disease, stroke, diabetes, heart failure, and chronic kidney disease.
FUNDING: National Institute for Health Research and Oxford Martin School.
BACKGROUND: The efficacy and safety of angiotensin receptor blockers (ARBs) in the older population is unclear.
OBJECTIVES: To determine the efficacy and safety of ARBs in older patients.
METHODS: Randomized trials that compared ARBs to control and reported clinical outcomes in patients with a mean age of 65 years or older were included. Random-effects summary risk ratios (RRs) were constructed.
RESULTS: A total of 16 trials met our selection criteria, which yielded 113,386 patients. ARBs were associated with a marginal increased risk of all-cause mortality (RR: 1.03, 95% confidence interval (CI): 1.00-1.06, P = 0.05), a nonsignificant increased risk of myocardial infarction (RR: 1.04, 95% CI: 0.96-1.12, P = 0.36), a marginal reduction in heart failure hospitalization (RR: 0.86, 95% CI: 0.74-1.00, P = 0.06), and a significant reduction in the risk of stroke (RR: 0.93, 95% CI: 0.87-0.99, P = 0.03). ARBs were associated with an increased risk of acute kidney injury (RR: 1.48, 95% CI: 1.24-1.77, P < 0.001), hypotension (RR: 1.56, 95% CI: 1.24-1.97, P < 0.001), and hyperkalemia (RR: 1.57, 95% CI: 1.13-2.19, P = 0.008). On the sensitivity analysis including placebo-controlled trials, the risk of all-cause mortality was no longer significant (P = 0.2), while the remainder of the outcomes did not change.
CONCLUSION: In older patients, the benefit of ARBs compared with control was strongest for stroke reduction, with no (or weak) associations for all-cause mortality, myocardial infarction, and heart failure hospitalization. Benefit was offset by an increased risk of acute kidney injury, hypotension, and hyperkalemia. Thus, ARBs should be used with caution in older patients when clinically indicated.
Renin-angiotensin-aldosterone system (RAAS) inhibition is 1 of the most effective strategies for the management of heart failure with reduced systolic function. However, trials that included patients with preserved systolic function have not shown a clear beneficial effect. Pooling evidence from several heart failure trials provides the opportunity to better assess the differential effects of RAAS inhibition across the continuum of systolic function. The authors searched MEDLINE for large-scale trials published from 1966 to March 2014 that compared RAAS inhibitors against placebos. Studies were eligible for inclusion if they were conducted in heart failure populations with either clinical signs of heart failure or reduced ejection fractions. Inverse variance-weighted fixed-effects meta-analysis was used to pool outcomes of interest, with metaregression used to test for trends. In 16 trials with 54,621 randomized heart failure participants, RAAS inhibition reduced the risks for hospitalization for heart failure by 20% (relative risk [RR] 0.80, 95% confidence interval [CI] 0.77 to 0.83), cardiovascular mortality by 14% (RR 0.86, 95% CI 0.83 to 0.90), and all-cause mortality by 11% (RR 0.89, 95% CI 0.85 to 0.92). However, proportional effects decreased with increasing mean left ventricular ejection fraction (LVEF) for all outcomes (p for trend <0.01). Although there was no significant proportional effect on cardiovascular and all-cause mortality in trials with a mean LVEF >50%, RAAS inhibition was still found to decrease the risk for heart failure hospitalization in patients with preserved LVEFs (RR 0.88, 95% CI 0.80 to 0.97). In conclusion, the relative beneficial effects of RAAS inhibition in heart failure decreases with increasing left ventricular systolic function. Nonetheless, RAAS inhibition significantly reduces the risks for all-cause mortality and cardiovascular mortality in patients with moderately reduced LVEFs and the incidence of hospitalization in patients with preserved left ventricular function.
Antihypertensive drugs are commonly used in cardiovascular diseases (CVD), less is known about the comparative effectiveness of different antihypertensive drugs on stroke events in CVD patients. We searched MEDLINE, EMBASE, the Cochrane Library, and the Web of Science for randomized controlled trails comparing the different antihypertensive drugs for stroke events in CVD patients from inception until November, 2022. Pairwise and network meta-analysis were performed to compare of different antihypertensive drugs for the incidence of stroke events in CVD patients. The protocol was registered on the PROSPERO database (CRD42022375038). 33 trials involving 141,217 CVD patients were included. The incidence of stroke in CVD patients for each antihypertensive drugs was placebo (3.0%), ACEI (2.4%), ARB (4.1%), CCB (1.8%), β blocker (1.3%), and diuretic (3.6%). Antihypertensive drug was significantly reducing stroke events in CVD patients when compared with placebo (OR 0.82; 95% CI 0.75 to 0.89). Specifically, ACEI (OR 0.82; 95% CI 0.69 to 0.97), ARB (OR 0.87; 95% CI 0.77 to 0.98), CCB (OR 0.69; 95% CI 0.54 to 0.87), and diuretic (OR 0.74; 95% CI 0.57 to 0.95) were significantly reducing stroke events in CVD patients when compared with placebo. Network meta-analysis suggested CCB and diuretic ranked the first and second in reducing the incidence of stroke events in CVD patients with the SUCRA value of 90.9% and 73.8%. CCB and diuretic had the greatest possibility to reduce the incidence of stroke events in CVD patients, while, ACEI was the worst antihypertensive agents in reducing the incidence of stroke events in CVD patients.
