Low-Dose Quadruple Antihypertensive Combination: More Efficacious Than Individual Agents-A Preliminary Report The use of baseline covariates in crossover studies. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. Randomized Polypill Crossover Trial in People Aged 50 and Over Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. A Simplified Approach to the Treatment of Uncomplicated Hypertension: A Cluster Randomized, Controlled Trial Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. TRIple pill vs Usual care Management for Patients with mild-to-moderate Hypertension (TRIUMPH): Study protocol. Effects of intensive blood-pressure control in type 2 diabetes mellitus. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. Effect of Intensive Versus Usual Blood Pressure Control on Kidney Function Among Individuals With Prior Lacunar Stroke: A Post Hoc Analysis of the Secondary Prevention of Small Subcortical Strokes (SPS3) Randomized Trial
Increasingly combined antihypertensive agents are being used in practice to enhance control and improve compliance . To determine whether a capsule containing a quarter of the st and ard dose of 4 antihypertensive agents has greater efficacy than the st and ard dose of each individually , we prospect ively r and omized 108 untreated white hypertensive patients ( 55 % male ) aged 50±1 years ( mean±SEM ) , with mean blood pressure 160±1/96±1 mm Hg . Patients received amlodipine ( 5 mg ; n=22 ) , atenolol ( 50 mg ; n=20 ) , bendroflumethiazide ( 2.5 mg ; n=22 ) , captopril ( 50 mg twice daily ; n=22 ) or a capsule containing each of the 4 above at one-quarter dosage ( n=22 ) in a parallel group design for 4 weeks . Blood pressure was measured using a semiautomated device ( Omron 705 ) , and the reduction in mean arterial pressure with the combined preparation was compared with that of the individual components . Statistical analysis used ANOVA and Tukey-Kramer honestly significant difference for multiple comparisons . The reduction in mean arterial pressure with the combination ( 19±2 mm Hg ) was significantly greater than that with individual agents  amlodipine ( 10±2 mm Hg ; P<0.005 ) , atenolol ( 10±2 mm Hg ; P<0.005 ) , bendroflumethiazide ( 6±1 mm Hg ; P<0.005 ) , and captopril ( 11±1 mm Hg ; P<0.01 ) . In addition , the percentage reduction in systolic ( 18±1 mm Hg ; P<0.005 ) and diastolic ( 17±2 mm Hg ; P=0.06 ) blood pressure was greater with the combination . More patients achieved a blood pressure of < 140/90 mm Hg with the combination ( 60 % ) than any individual drug ( 15 % to 45 % ; P<0.05 ) . A low-dose combination of 4 agents representing 4 classes of st and ard antihypertensive agents was more efficacious than a st and ard single dose of each agent individually It is our experience that in many setting s , crossover trials that have within-period baseline measurements are analyzed wrongly . A " conventional " analysis of covariance in this setting uses each baseline as a covariate for the following outcome variable in the same period but not for any other outcome . If used with r and om subject effects such an analysis leads to biased treatment comparisons ; this is an example of cross-level bias . Using a postulated covariance structure that reflects the symmetry of the crossover setting , we quantify such bias and , at the same time , investigate potential gains and losses in efficiency through the use of the baselines . We then describe alternative methods of analysis that avoid the cross-level bias . The development is illustrated throughout with 2 example trials , one balanced and orthogonal and one highly unbalanced and nonorthogonal . BACKGROUND It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure . METHODS We r and omly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan ( 300 mg daily ) , amlodipine ( 10 mg daily ) , or  placebo .  The target blood pressure was 135/85 mm Hg or less in all groups . We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration , the development of end-stage renal disease , or death from any cause . We also compared them with regard to the time to a secondary , cardiovascular composite end point . RESULTS The mean duration of follow-up was 2.6 years . Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group ( P=0.02 ) and 23 percent lower than that in the amlodipine group ( P=0.006 ) . The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group ( P=0.003 ) and 37 percent lower in the irbesartan group than in the amlodipine group ( P<0.001 ) . Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups ( P=0.07 for both comparisons ) . These differences were not explained by differences in the blood pressures that were achieved . The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group ( P=0.008 ) and 21 percent more slowly than in the amlodipine group ( P=0.02 ) . There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point . CONCLUSIONS The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes . This protection is independent of the reduction in blood pressure it causes Background A Polypill is proposed for the primary prevention of cardiovascular disease in people judged to be at risk on account of their age alone . Its efficacy in reducing cholesterol and blood pressure is uncertain . Methods We conducted a r and omized double-blind placebo-controlled crossover trial of a Polypill among individuals aged 50 + without a history of cardiovascular disease and compared the reductions with those predicted from published estimates of the effects of the individual drugs . Participants took the Polypill ( amlodipine 2.5 mg , losartan 25 mg , hydrochlorothiazide 12.5 mg and simvastatin 40 mg ) each evening for 12 weeks and a placebo each evening for 12 weeks in r and om sequence . The mean within-person differences in blood pressure and low density lipoprotein ( LDL ) cholesterol at the end of each 12 week period were determined . Results 84 out of 86 participants completed both treatment periods . The mean systolic blood pressure was reduced by 17.9 mmHg ( 95 % CI , 15.7–20.1 ) on the Polypill , diastolic blood pressure by 9.8 mmHg ( 8.1–11.5 ) , and LDL cholesterol by 1.4 mmol/L ( 1.2–1.6 ) , reductions of 12 % , 11 % , and 39 % respectively . The results were almost identical to those predicted ; 18.4 mmHg , 9.7 mmHg , and 1.4 mmol/L respectively . Conclusion The Polypill result ed in the predicted reductions in blood pressure and LDL cholesterol . Long term reductions of this magnitude would have a substantial effect in preventing heart attacks and strokes . Trial Registration Controlled-Trials.com IS RCT CONTEXT Hypertension is a leading cause of end-stage renal disease ( ESRD ) in the United States , with no known treatment to prevent progressive declines leading to ESRD . OBJECTIVE To compare the effects of 2 levels of blood pressure ( BP ) control and 3 antihypertensive drug classes on glomerular filtration rate ( GFR ) decline in hypertension . DESIGN R and omized 3 x 2 factorial trial with enrollment from February 1995 to September 1998 . SETTING AND PARTICIPANTS A total of 1094 African Americans aged 18 to 70 years with hypertensive renal disease ( GFR , 20 - 65 mL/min per 1.73 m(2 ) ) were recruited from 21 clinical centers throughout the United States and followed up for 3 to 6.4 years . INTERVENTIONS Participants were r and omly assigned to 1 of 2 mean arterial pressure goals , 102 to 107 mm Hg ( usual ; n = 554 ) or 92 mm Hg or less ( lower ; n = 540 ) , and to initial treatment with either a beta-blocker ( metoprolol 50 - 200 mg/d ; n = 441 ) , an angiotensin-converting enzyme inhibitor ( ramipril 2.5 - 10 mg/d ; n = 436 ) or a dihydropyridine calcium channel blocker , ( amlodipine 5 - 10 mg/d ; n = 217 ) . Open-label agents were added to achieve the assigned BP goals . MAIN OUTCOME MEASURES Rate of change in GFR ( GFR slope ) ; clinical composite outcome of reduction in GFR by 50 % or more ( or > or = 25 mL/min per 1.73 m2 ) from baseline , ESRD , or death . Three primary treatment comparisons were specified : lower vs usual BP goal ; ramipril vs metoprolol ; and amlodipine vs metoprolol . RESULTS Achieved BP averaged ( SD ) 128/78 ( 12/8 ) mm Hg in the lower BP group and 141/85 ( 12/7 ) mm Hg in the usual BP group . The mean ( SE ) GFR slope from baseline through 4 years did not differ significantly between the lower BP group ( -2.21 [ 0.17 ] mL/min per 1.73 m2 per year ) and the usual BP group ( -1.95 [ 0.17 ] mL/min per 1.73 m2 per year ; P = .24 ) , and the lower BP goal did not significantly reduce the rate of the clinical composite outcome ( risk reduction for lower BP group = 2 % ; 95 % confidence interval [ CI ] , -22 % to 21 % ; P = .85 ) . None of the drug group comparisons showed consistent significant differences in the GFR slope . However , compared with the metoprolol and amlodipine groups , the ramipril group manifested risk reductions in the clinical composite outcome of 22 % ( 95 % CI , 1%-38 % ; P = .04 ) and 38 % ( 95 % CI , 14%-56 % ; P = .004 ) , respectively . There was no significant difference in the clinical composite outcome between the amlodipine and metoprolol groups . CONCLUSIONS No additional benefit of slowing progression of hypertensive nephrosclerosis was observed with the lower BP goal . Angiotensin-converting enzyme inhibitors appear to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline Notwithst and ing the availability of antihypertensive drugs and practice guidelines , blood pressure control remains suboptimal . The complexity of current treatment guidelines may contribute to this problem . To determine whether a simplified treatment algorithm is more effective than guideline -based management , we studied 45 family practice s in southwestern Ontario , Canada , using a cluster r and omization trial comparing the simplified treatment algorithm with the Canadian Hypertension Education Program guidelines . The simplified treatment algorithm consisted of the following : ( 1 ) initial therapy with a low-dose angiotensin-converting enzyme inhibitor/diuretic or angiotensin receptor blocker/diuretic combination ; ( 2 ) up-titration of combination therapy to the highest dose ; ( 3 ) addition of a calcium channel blocker and up-titration ; and ( 4 ) addition of a non — first-line antihypertensive agent . The proportion of patients treated to target blood pressure ( systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg for patients without diabetes mellitus or systolic blood pressure < 130 mm Hg and diastolic blood pressure < 80 mm Hg for diabetic patients ) at 6 months was analyzed at the practice level . The proportion of patients achieving target was significantly higher in the intervention group ( 64.7 % versus 52.7 % ; absolute difference : 12.0 % ; 95 % CI : 1.5 % to 22.4 % ; P=0.026 ) . Multivariate analysis of patient-level data showed that assignment to the intervention arm increased the chance of reaching the target by 20 % ( P=0.028 ) , when adjusted for other covariates . In conclusion , the Simplified Treatment Intervention to Control Hypertension Study indicates that a simplified antihypertensive algorithm using initial low-dose fixed-dose combination therapy is superior to guideline -based practice for the management of hypertension The Modification of Diet in Renal Disease ( MDRD ) Study examined the effects of dietary protein restriction and strict blood pressure control on the decline in glomerular filtration rate ( GFR ) in 840 patients with diverse renal diseases . We describe a systematic analysis to determine baseline factors that predict the decline in GFR , or which alter the efficacy of the diet or blood pressure interventions . Univariate analysis identified 18 of 41 investigated baseline factors as significant ( P < 0.05 ) predictors of GFR decline . In multivariate analysis , six factors -- greater urine protein excretion , diagnosis of polycystic kidney disease ( PKD ) , lower serum transferrin , higher mean arterial pressure , black race , and lower serum HDL cholesterol -- independently predicted a faster decline in GFR . Together with the study interventions , these six factors accounted for 34.5 % and 33.9 % of the variance between patients in GFR slopes in Studies A and B , respectively , with proteinuria and PKD playing the predominant role . The mean rate of GFR decline was not significantly related to baseline GFR , suggesting an approximately linear mean GFR decline as renal disease progresses . The 41 baseline predictors were also assessed for their interactions with the diet and blood pressure interventions . A greater benefit of the low blood pressure intervention was found in patients with higher baseline urine protein . None of the 41 baseline factors were shown to predict a greater or lesser effect of dietary protein restriction BACKGROUND Hypertension management strategies have traditionally focused on " tailored therapy " and " stepped-care " approaches . These tend to be costly and time consuming and often fail to achieve adequate blood pressure ( BP ) control . The TRIUMPH study aims to investigate the effectiveness , cost-effectiveness , and acceptability of early use of a 3-in-1 BP-lowering pill ( " Triple Pill " ) compared with usual care for the management of hypertension . METHODS The prospect i ve , open , r and omized controlled clinical trial ( n = 700 ) will compare Triple Pill-based strategy to usual care among individuals with persistent mild-to-moderate hypertension ( systolic BP > 140 mm Hg and /or diastolic BP > 90 mm Hg , or systolic BP > 130 mm Hg and /or diastolic BP > 80 mm Hg in patients with diabetes or chronic kidney disease ) on no or minimal drug therapy . The study will be conducted within approximately 20 hospital-based clinics in India . Participants will be r and omized to the Triple Pill ( initially strength 1-telmisartan 20 mg , amlodipine 2.5 mg , hydrochlorothiazide 6.25 mg , with the option of subsequent titration to strength 2-telmisartan 40 mg , amlodipine 5 mg , hydrochlorothiazide 12.5 mg ) or continued usual care . Participants will be followed up for 6 months . The primary outcome is the proportion of participants achieving target BP at the end follow-up . CONCLUSION This study will determine whether early use of a low-dose triple combination therapy has the potential to address some of the challenges in hypertension control through earlier achievement of BP control , better adherence , and fewer adverse effects , in the context of less intensive clinical follow-up BACKGROUND There is no evidence from r and omized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus . We investigated whether therapy targeting normal systolic pressure ( i.e. , < 120 mm Hg ) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events . METHODS A total of 4733 participants with type 2 diabetes were r and omly assigned to intensive therapy , targeting a systolic pressure of less than 120 mm Hg , or st and ard therapy , targeting a systolic pressure of less than 140 mm Hg . The primary composite outcome was nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes . The mean follow-up was 4.7 years . RESULTS After 1 year , the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the st and ard-therapy group . The annual rate of the primary outcome was 1.87 % in the intensive-therapy group and 2.09 % in the st and ard-therapy group ( hazard ratio with intensive therapy , 0.88 ; 95 % confidence interval [ CI ] , 0.73 to 1.06 ; P=0.20 ) . The annual rates of death from any cause were 1.28 % and 1.19 % in the two groups , respectively ( hazard ratio , 1.07 ; 95 % CI , 0.85 to 1.35 ; P=0.55 ) . The annual rates of stroke , a prespecified secondary outcome , were 0.32 % and 0.53 % in the two groups , respectively ( hazard ratio , 0.59 ; 95 % CI , 0.39 to 0.89 ; P=0.01 ) . Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group ( 3.3 % ) and 30 of the 2371 participants in the st and ard-therapy group ( 1.3 % ) ( P<0.001 ) . CONCLUSIONS In patients with type 2 diabetes at high risk for cardiovascular events , targeting a systolic blood pressure of less than 120 mm Hg , as compared with less than 140 mm Hg , did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events . ( Clinical Trials.gov number , NCT00000620 . IMPORTANCE Hypertension is the most important preventable cause of morbidity and mortality globally , yet there are relatively few data collected using st and ardized methods . OBJECTIVE To examine hypertension prevalence , awareness , treatment , and control in participants at baseline in the Prospect i ve Urban Rural Epidemiology ( PURE ) study . DESIGN , SETTING , AND PARTICIPANTS A cross-sectional study of 153,996 adults ( complete data for this analysis on 142,042 ) aged 35 to 70 years , recruited between January 2003 and December 2009 . Participants were from 628 communities in 3 high-income countries ( HIC ) , 10 upper-middle-income and low-middle-income countries ( UMIC and LMIC ) , and 4 low-income countries ( LIC ) . MAIN OUTCOMES AND MEASURES Hypertension was defined as individuals with self-reported treated hypertension  or with an average of 2 blood pressure measurements of at least 140/90 mm Hg using an automated digital device . Awareness was based on self-reports , treatment was based on the regular use of blood pressure-lowering medications , and control was defined as individuals with blood pressure lower than 140/90 mm Hg . RESULTS Among the 142,042 participants , 57,840 ( 40.8 % ; 95 % CI , 40.5%-41.0 % ) had hypertension and 26,877 ( 46.5 % ; 95 % CI , 46.1%-46.9 % ) were aware of the diagnosis . Of those who were aware of the diagnosis , the majority ( 23,510 [ 87.5 % ; 95 % CI , 87.1%-87.9 % ] of those who were aware ) were receiving pharmacological treatments , but only a minority of those receiving treatment were controlled ( 7634 [ 32.5 % ; 95 % CI , 31.9%-33.1 % ] ) . Overall , 30.8 % , 95 % CI , 30.2%-31.4 % of treated patients were taking 2 or more types of blood pressure-lowering medications . The percentages aware ( 49.0 % [ 95 % CI , 47.8%-50.3 % ] in HICs , 52.5 % [ 95 % CI , 51.8%-53.2 % ] in UMICs , 43.6 % [ 95 % CI , 42.9%-44.2 % ] in LMICs , and 40.8 % [ 95 % CI , 39.9%-41.8 % ] in LICs ) and treated ( 46.7 % [ 95 % CI , 45.5%-47.9 % ] in HICs , 48.3 % , [ 95 % CI , 47.6%-49.1 % ] in UMICs , 36.9 % , [ 95 % CI , 36.3%-37.6 % ] in LMICs , and 31.7 % [ 95 % CI , 30.8%-32.6 % ] in LICs ) were lower in LICs compared with all other countries for awareness ( P < .001 ) and treatment ( P < .001 ) . Awareness , treatment , and control of hypertension were higher in urban communities compared with rural ones in LICs ( urban vs rural , P < .001 ) and LMICs ( urban vs rural , P < .001 ) , but similar for other countries . Low education was associated with lower rates of awareness , treatment , and control in LICs , but not in other countries . CONCLUSIONS AND RELEVANCE Among a multinational study population , 46.5 % of participants with hypertension were aware of the diagnosis , with blood pressure control among 32.5 % of those being treated . These findings suggest substantial room for improvement in hypertension diagnosis and treatment Background — The effect of intensive blood pressure ( BP ) lowering on kidney function among individuals with established cerebrovascular disease and preserved estimated glomerular filtration rate ( eGFR ) is not established . Methods and Results — Among 2610 participants r and omized to a lower ( < 130 mm Hg ) versus higher ( 130–149 mm Hg ) systolic BP target with repeated measures of serum creatinine , we evaluated differences by study arm in annualized eGFR decline and rapid decline ( eGFR decline > 30 % ) using linear mixed models and logistic regression , respectively . We assessed associations of both treatment and kidney function decline with stroke , major vascular events , and the composite of stroke , death , major vascular events , or myocardial infa rct ion using multivariable Cox regression , separately and jointly including a test for interaction . Analyses were conducted by treatment arm . Mean age was 63±11 years ; 949 participants ( 36 % ) were diabetic ; and mean eGFR was 80±19 mL·min−1·1.73 m−2 . At 9 months , achieved systolic BP was 137±15 versus 127±14 mm Hg in the higher versus lower BP group , and differences were maintained throughout follow-up ( mean , 3.2 years ) . Compared with the higher target , the lower BP target had a −0.50–mL·min−1·1.73 m−2 per year ( 95 % confidence interval [ CI ] , −0.79 to −0.21 ) faster eGFR decline . Differences were most pronounced during the first year ( −2.1 mL·min−1·1.73 m−2 ; 95 % CI , −0.97 to −3.2 ) , whereas rates of eGFR decline did not differ after year 1 ( −0.095 ; 95 % CI , −0.47 to 0.23 ) . A total of 313 patients ( 24 % ) in the lower BP group had rapid kidney function decline compared with 247 ( 19 % ) in the higher BP group ( odds ratio , 1.4 ; 95 % CI , 1.1–1.6 ) . Differences in rapid decline by treatment arm were apparent in the first year ( odds ratio , 1.4 ; 95 % CI , 1.1–1.8 ) but were not significant after year 1 ( odds ratio , 1.0 ; 95 % CI , 0.73–1.4 ) . Rapid decline was associated with higher risk for stroke , major vascular events , and composite after full adjustment among individuals r and omized to the higher BP target ( stroke hazard ratio , 1.93 ; 95 % CI , 1.15–3.21 ) but not the lower BP arm ( stroke hazard ratio , 0.93 ; 95 % CI , 0.50–1.75 ; all P for interaction < 0.06 ) . Conclusions — In patients with prior lacunar stroke and relatively preserved kidney function , intensive BP lowering was associated with a greater likelihood of rapid kidney function decline . Differences were observed primarily during the first year of antihypertensive treatment . Rapid kidney function decline was not associated with increased risk for clinical events among those undergoing intensive BP lowering . Clinical Trial Registration — URL : http://www . clinical Trials.gov . Unique identifier : NCT00059306
BACKGROUND Globally , most patients with hypertension are treated with monotherapy , and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on average .
There is a pressing need for blood pressure-control strategies with improved efficacy and tolerability .
We aim ed to assess whether ultra-low-dose combination therapy could meet these needs .